IMR Press / FBL / Volume 28 / Issue 1 / DOI: 10.31083/j.fbl2801021
Open Access Review
Transgenic Mouse Models for the Study of Neurodegenerative Diseases
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1 Centro de Investigación en Sanidad Animal (CISA), Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA) – Consejo Superior de Investigaciones Científicas (CSIC), 28130 Valdeolmos, Spain
*Correspondence: (Juan María Torres)
Academic Editors: Fabio Moda and Giorgio Giaccone
Front. Biosci. (Landmark Ed) 2023, 28(1), 21;
Submitted: 7 December 2022 | Revised: 28 December 2022 | Accepted: 5 January 2023 | Published: 19 January 2023
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Neurodegenerative diseases (NDs) are some of the most important health challenges modern medicine and advanced societies face. Indeed, the number of patients affected by one of these illnesses will increase in the following years at the same rate that human life expectancy allows us to live longer. Despite many years of research, NDs remain invariably fatal. A complete understanding of the exact mechanisms leading to neuronal death, which will ideally allow preclinical detection and the development of effective treatments, has not yet been achieved. However, a great deal of information about ND pathology and the search for possible therapies has been acquired using animal models and more precisely transgenic mouse models. In this review, the main contributions of these powerful research tools in NDs as well as their advantages and caveats are discussed.

neurodegenerative diseases
transgenic mice
1. Introduction

Human life has been extended in the last decades thanks to modern medicine and general improvement in human life quality. However, the increase in our life expectancy has resulted in a new major challenge for human health: neurodegenerative diseases (ND) in the elderly. Diseases involving the loss of nerve cells are currently a main problem in the aging population worldwide, which will go worse since a further rise in human longevity is expected, especially in developed countries. For instance, Alzheimer’s disease (AD) is believed to affect around 40 million people worldwide and its prevalence is expected to reach 135 million people by 2050 [1]. In addition, NDs truly disable patients causing great suffering to them, their relatives, and their caretakers affecting seriously not only the physical but also the mental health of all people involved.

Despite the huge amounts of funds, human effort, and the years passed, NDs do not have an effective treatment. Few drugs for treating symptoms at the beginning of the disease course have been approved. For example, the L-DOPA-based treatment of Parkinson’s disease (PD) therapies substitutes dopamine precursors due to the death of dopaminergic neurons, but its efficiency is temporal and limited [2]. The lack of success in the search for ND’s treatment is partially influenced by the incubation time of NDs. The molecular events that trigger neuron death start years (even decades) before symptom appearance. Central nervous system (CNS) plasticity, which allows neuronal web reconnection and reconfiguration when cells die to maintain the system function, disguises the disease. Thus, NDs might be already irreversible at symptom onset. A possible option to improve the chances of successful therapies will be to direct them to the preclinical phase of these diseases, although treatment after the onset of clinical symptoms is the most common scenario in NDs. Such situations point out the need for models for NDs, both to understand the basis of the underlying pathology and to test potential drugs.

Most common NDs share in the center of their pathology the aggregation of a misfolded protein, as well as an unknown and complicated etiology in the majority of the patients. The first animal models for the study of NDs were knock-out (KO) mice, aimed to recapitulate the loss-of-function of the genes coding the proteins that get aggregated. Mice’s advantages concerning other animals include their small size, short lifespan and generation time, easy manipulation, and availability of well-established molecular biology techniques that allow genetic manipulation. In addition, many tests aimed to check several aspects of human behavior have been established and normalized in rodents. Thus, transgenic mice have been implemented as the preferred animal model for the study of NDs. The later development of homologous recombination-mediated genetic engineering further facilitated transgenic mice creation [3] by targeting particular cell populations and allowing spatiotemporal expression of the transgenes. The existence of genetically inherited forms of certain NDs also facilitated the generation of transgenic mice models for disease study and therapy assessment. However, a general problem with transgenic mice models of NDs is that they often do not completely recapitulate the whole human phenotype, making the available models just partially useful. The very recent development of the simple and powerful CRISPR-Cas9 for gene editing is called to revolutionize and improve transgenic animal creation [4]. New models for NDs are already being produced by this technique and their utility shall therefore be compared to that of the currently existing ones in the future.

This review aims to compile the most relevant transgenic mice models for several NDs, their success and pitfalls, and discuss the currently unsolved problems in NDs modeling.

2. Transgenic Mouse Models for the Study of Synucleinopathies

Synucleinopathies are a group of NDs which are molecularly characterized by the CNS accumulation of α-synuclein (α-syn) intracytoplasmic inclusions. Synucleinopathies include Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA). Although α-syn is involved in all cases, the most affected brain areas and specific cell types differ between diseases, influencing the clinical signs associated with each pathology.

2.1 Parkinson’s Disease (PD)

PD is the most prevalent synucleinopathy [5] and the most common ND movement disorder, affecting around 1.2 million people in Europe [6]. It was predicted that around 9 million people worldwide will be affected by PD in 2030 [7]. PD is characterized by motor symptoms like rigidity, tremor, postural instability, and bradykinesia due to the loss of dopaminergic neurons in the substantia nigra pars compacta projecting to the CNS striatum [8]. Other non-motor symptoms include lack of motivation, depression, sleep disorders, cognitive impairment, loss of smell, and constipation [9, 10, 11]. α-syn inclusions detected in the cytoplasm of neurons, Lewy Bodies (LBs), are the major histopathological hallmark of PD [12, 13, 14]. In addition, α-syn inclusions can be found in so-called Lewy neurites (LNs) [14]. In healthy individuals, α-syn is located at great amounts in the presynaptic terminals in equilibrium between monomeric, oligomeric, and aggregated forms [15]. However, in PD patients, LBs and LNs form and spread through neurons [16, 17, 18]. Current evidence supports that LBs and LNs are not the toxic components responsible for neuron death, but may cause functional deficits [19, 20].

Most PD cases are of unknown etiology, however, there are familial forms of PD that correlate with mutations in several genes such as SNCA, PARK2, UCHL1, PINK1, DJ-1, and LRRK2 [21, 22]. Familial forms of PD only account for 5%–10% of PD cases [23, 24]. There are no clear reasons why the dopaminergic neurons die, but several molecular mechanisms have been pointed to be involved in PD pathology like mitochondrial dysfunction, proteostasis, lysosomal and autophagy failures, oxidative stress, and neuroinflammation [25, 26, 27, 28].

Transgenic mouse models for the study of PD rely on the modeling of early-onset genetic forms of PD. Detailed information on all models listed below can be found at Surprisingly, introducing mutations known to cause PD in humans in mice only produces mild neurodegeneration and smooth phenotype (Table 1, Ref. [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51]). Some models were proposed as useful to model early prodromal stages of PD due to their soft phenotypes characterized by mild functional impairments. However, a deep comparison of mutant LRRK2-R1441G mice as well as DJ-1, PINK1, and PARK2 KO mice with wild-type controls did not detect differences in dopamine release [52]. It must be noted that other rodent models for PD study exist, relying on the use of neurotoxins like 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or aggregated α-syn injections to induce the loss of dopaminergic neurons in the substantia nigra.

Table 1.Transgenic mouse models of Parkinson’s disease (PD).
Gene Generation technique Name Promoter Construct Neuronal loss (substantia nigra) α-syn protein deposition Clinical signs Reference
SNCA Transgenic-Microinjection α-synuclein A30P/A53T Mouse (Tg) Th (rat) SNCA (A30P/A53T) Yes No Atrophic axons and dendrites in the dopaminergic system, reduced motor coordination [32]
α-synuclein A53T Mouse (Tg) Prnp SNCA (A53T) No Yes Alterations in dopaminergic-associated proteins in some brain areas, accumulation of ubiquitin and neurofilament-H, astrocytosis, severe motor impairment, memory impairment, premature death [33]
Thy1-αSyn “Line 61” Mouse Thy1 SNCA No Yes None [34]
Transgenic-Knock out α-synuclein KO Mouse Snca Snca interruption (neomycin) No No Abnormal regulation in synaptic vesicle mobilization at nerve terminals [29]
α-synuclein KO Mouse (Conditional) Snca Snca interruption (Cre-LoxP system) No No None [30, 31]
LRRK2 Transgenic-Microinjection LRRK2 G2019S Mouse (BAC Tg) Lrrk2 Lrrk2 (G2019S) No No Decreased striatal dopamine content, decreased evoked release [35]
LRRK2 G2019S Mouse (Tg) CMVe-PDGFβ LRRK2 (G2019S) Yes No Abnormal mitochondria in striatal neurons and microglia, activated microglia in striatum, anxiety/depression like behavior in middle age [36]
LRRK2 R1441C Mouse (Tg - Conditional) ROSA26 (conditional) LRRK2 (R1441C) No No Subtle morphological abnormalities in neuronal nuclei [37]
LRRK2 R1441G Mouse (BAC Tg) Lrrk2 LRRK2 (R1441G) No No Age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection [38]
DJ-1 Transgenic-Knock out DJ-1 Null Mice Dj-1 Dj-1 first 5 exons and part of the promoter deletion No No Age-dependent and task-dependent motoric behavioral deficits ,changes in striatal dopaminergic function [39]
DJ-1/ Dj-1 Dj-1 exon 2 replacement (neomycin) No No Progressive behavioral changes without significant alterations in nigrostriatal dopaminergic and spinal motor systems [40]
DJ-1/ Mice Dj-1 Dj-1 exon 2 replacement (neomycin) No No Alterations in nigrostriatal dopaminergic and spinal motor systems [41]
DJ1-C57 Dj-1 Dj-1 null mice backcrossed 14 times onto a pure C57BL/6J background Yes No Aging-dependent bilateral degeneration of the nigrostriatal axis and nucleus ceruleus, mild motor behavior deficits [42]
DJ-1 KO Mice Dj-1 Dj-1 exon 2-3 replacement (neomycin) No No The mice are anatomically and behaviorally similar to WT mice [43]
DJ-1/ Dj-1 Dj-1 exon 3-5 replacement (neomycin) No No The mice are anatomically and behaviorally similar to WT mice [44]
PINK1 Transgenic-Knock in PINK1 G309D (PINK1-/-) Mouse (KI) Pink1 Pink1 (G309D) No No Mitochondrial dysfunction, electrophysiological abnormalities, subtle alterations in gene expression in brain areas [45]
Transgenic-Knock out PINK1 KO Mouse Pink1 Pink1 interruption (PGK-Neo) No No Heavier than wildtype mice at 5 months, subtle plasticity abnormalities [46]
PARK2 Transgenic-Knock out Parkin-/- Mice Park2 Park2 exon 3 replacement (EGF-PGK-neo) No No Reduction in synaptic excitability, deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway [47]
Parkin mutant mice Park2 Park2 exon 3 and intron 4 replacement (neomycin) No No Motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission [48, 49]
Parkin Null Mice Park2 Park 2 exon 7 deletion (Cre-LoxP system) No No Loss of catecholaminergic neurons in the locus coeruleus, loss of norepinephrine in discrete regions of the brain [50]
DJ-1, PINK1, PARK2 Transgenic-Knock out TKO mice Dj-1/Pink1/Park2 Crossing of DJ-1/ Mice, PINK1 KO Mouse and Parkin-/- Mice No No Levels of striatal dopamine increased at 24 months [51]
2.1.1 Alpha-Synuclein (SNCA)

Mutations in the SNCA gene that cause genetic PD in humans are transmitted by autosomal dominant inheritance. To date, six disease-causing mutations have been identified: A30P, E46K, H50Q, G51D, A53T, and A53E, all located in the N-terminal region of the α-syn protein. In general terms, transgenic mouse lines for the SNCA gene show little loss of dopaminergic neurons but the aggregation of α-synuclein is more frequently found (Table 1). The development of motor and non-motor symptoms is also highly variable and model dependent. Given the variety of different promoters used and mutations modeled, the lack of a proper model seems to be related to intrinsic differences in how humans and mice dopaminergic neurons react to mutations in the SNCA gene. For instance, wild-type mice normally harbor a T in position 53 which in humans is associated with the genetic development of PD. In addition, the mice substrain C57B1/6OlaHsd naturally lack α-syn expression, being normal [53]. This phenomenon was also observed in transgenic mice genetically engineered to not express the SNCA gene [29, 30, 31], although one line exhibited abnormalities in synaptic morphology and function, along with fairly subtle behavioral changes [29].

2.1.2 Leucine-Rich Repeat Kinase 2 (LRRK2)

Mutations in the LRRK2 gene that cause genetic PD in humans are transmitted by autosomal dominant inheritance and are the most prevalent genetic cause of PD. They are associated with PD classical clinical features and a late-onset of the disease. Only a few mutations have been linked to the disease (G2019S, R1441C, R1441G, R141H, I2020T, and Y1699C) but many others have been identified as risk factors (over 40 different mutations). LRRK2 has been linked to various possible pathogenic mechanisms including α-syn and tau aggregation, inflammation, oxidative stress, and mitochondrial, synaptic, and autophagy-lysosomal dysfunctions [54]. None of the transgenic lines generated for the LRRK2-associated PD recapitulates the human PD phenotype, regardless of the mutation modeled (Table 1). Relatively successful models achieved α-syn aggregation and development of motor symptoms but no neurodegeneration or neurodegeneration plus motor symptoms and no α-syn aggregation.

2.1.3 Protein Deglycase DJ-1 (DJ-1)

Mutations in DJ-1 have been identified in autosomal recessive forms of early-onset PD. These mutations involve loss of function missense mutations and large deletions [55]. KO mice for the DJ-1 gene do not recapitulate the human PD phenotype (Table 1). No clear motor symptoms, α-syn aggregation, and neuron loss have been detected [39, 40] but subtle dysfunctions have been reported in a few models [39, 40, 41, 42]. However, DJ-1 KO mice have been useful to study the role of the DJ-1 protein, which has been related to mitochondrial function [43, 44].

2.1.4 Phosphatase and Tensin Homolog (PTEN)-Induced Kinase 1 (PINK1)

Recessive mutations in the PINK1 gene cause early-onset PD being the second-commonest cause of autosomal recessive early-onset PD. KO mice for the PINK1 gene did not develop a ND but show impaired mitochondrial and neuronal function [45, 56, 57, 46]. The most important models are included in Table 1.

2.1.5 Parkin (PARK2)

The PARK2 gene, coding for the Parkin or ubiquitin E3 ligase protein, was the first gene associated with autosomal recessive PD. More than fifty different mutations in the PARK2 gene cause PD. As mentioned above, with other genes, PARK2 KO in mice did not produce a clear PD phenotype. Models just showed partial and mild signs of PD like deficits in the dopamine system and motor symptoms, but none or only moderate loss of dopaminergic neurons was detected [58, 47, 48, 49, 50]. However, noradrenergic neurons in the locus coeruleus were found to degenerate in other PARK2 KO models [59]. The most important models are included in Table 1.

2.1.6 Combined Models

Since Parkin, PINK1, and DJ-1 proteins conform to a ubiquitin E3 ligase protein complex, a triple KO mouse lacking expression of the three genes was generated (Table 1). Unfortunately, this complex model did not present neuron degeneration [51].

2.2 Multiple System Atrophy (MSA)

MSA is rarer than the other synucleinopathies [60] and is clinically divided into two subtypes based on different phenotypes, parkinsonian MSA or MSA-P (associated with the loss of nigrostriatal dopaminergic neurons) and cerebellar MSA or MSA-C (associated with the loss of olivopontocerebellar neurons). While MSA-P patients show more typical PD symptoms, MSA-C patients develop cerebellar ataxia. PD and MSA are clinically quite similar and although differential diagnosis based on clinical symptoms is possible, neuropathological confirmation is necessary for a definitive MSA diagnosis. In MSA pathology, oligodendrocytes play the main role due to the presence of α-syn intracytoplasmic inclusions named glial cytoplasmic inclusions (GCI) which are used as main the neuropathological hallmark for MSA diagnosis [61]. GCIs are spherical protein aggregates composed mainly of phosphorylated α-syn.

As mentioned before for PD, there are MSA models that rely on neurotoxins to induce the loss of dopaminergic neurons in the substantia nigra. Apart from 6-OHDA and MPTP, quinolinic acid, 3-nitropropionic acid (3-NP) and 1-methyl-4-phenylpyridinium ion (MPP+) can be used to produce pathology in the nigrostriatal system [62, 63, 64, 65, 66, 67, 68, 69]. Nevertheless, it must be noted that the generated pathology does not transmit outside the basal ganglia and does not induce the formation of GCIs [70].

Transgenic mouse models for the study of MSA have been generated by driving mutated or wild-type α-syn expression to oligodendrocytes using specific promoters. In general lines, transgenic mouse lines that overexpress α-syn in their oligodendrocytes show motor and non-motor symptoms as well as oligodendroglial α-syn aggregates resembling human GCIs (Table 2, Ref. [71, 72, 73, 74, 75, 76, 77, 78]). Interestingly, promoter election for the transgenic generation seems to impact the phenotypes shown by the different transgenic lines and none of them fully replicate the two differentiated human MSA phenotypes.

Table 2.Transgenic mouse models of multiple system atrophy (MSA).
Gene Generation technique Name Promoter Construct Dopaminergic neuron loss α-syn protein deposition Clinical signs Reference
SNCA Transgenic-Microinjection PLP-αsyn PLP SNCA Yes Yes Ser129 α-syn phosphorylation, GCI-like inclusions, gliosis, cytokine production, motor symptoms, autonomic symptoms [71, 72, 73, 74, 75]
MBP29-hα-syn MBP SNCA Yes Yes Ser129 α-syn phosphorylation, GCI-like inclusions, astrogliosis, neuroinflammation, cytokine production, demyelination, motor symptoms, behavioral symptoms, premature death of a higher expressor line [76, 77]
M2 mice CNP SNCA Yes Yes Ser129 α-syn phosphorylation, GCI-like inclusions, gliosis, demyelination, motor symptoms [78]
3. Transgenic Mouse Models for the Study of Non-Alzheimer Tauopathies

Tauopathies are NDs characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in neurofibrillary tangles (NFTs) and paired helical filaments (PHFs) that cause the death of affected neurons and glial cells. Tauopathies include frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration syndrome (CBS), chronic traumatic encephalopathy (CTE), Pick’s disease, and sporadic forms of AD. Some of them are inherited by mutations in the MAPT gene [79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93]. Given that AD has other molecular hallmarks and is the most common form of ND, the models for its study will address separately, being this part focused on other non-Alzheimer tauopathies.

MAPT is a neuronal protein involved in the regulation of microtubule stability, microtubule dynamics, and axonal transport [94, 95]. Many MAPT mutations cause the inheritance of genetic forms of tauopathies supposedly by increasing tau’s propensity for aggregation and toxicity [96]. Nevertheless, as reported with other NDs, the majority of tauopathies are sporadic, and variable clinical and pathological presentations have been described in patients [79]. The mechanisms of tau aggregation as well as the disruption of molecular pathways that ultimately cause cell death are still poorly understood. Evidence indicates that native tau is soluble, contains charged and hydrophilic residues, and shows little tendency for aggregation [97, 98, 99]. Thus, to aggregate, tau must undergo conformational and post-translational modifications like phosphorylation [100, 101, 102, 103]. It has been reported that phosphorylation at certain residues like Ser422 is rarely detected in healthy adults [104] but is present in AD patients and related to loss of cholinergic neurons and cognitive impairment [105, 106].

Frontotemporal Dementia (FTD)

Several related disorders are included in the spectrum of FTD. Among the different clinical diagnoses, the most common one is behavioral variant FTD (bvFTD) [107]. Even in the category of bvFTD, pathological heterogeneity is a common phenomenon, since several misfolded proteins have been found to aggregate and cause frontotemporal lobar degeneration in patients. One of these misfolded proteins is tau. The neuropathological term for cases with tau pathology is Frontotemporal lobar degeneration (FTLD)-tau and the clinical term for cases with MAPT mutations in frontotemporal dementia and parkinsonism linked to chromosome 17, tau gene (FTDP-17T). Patients with MAPT mutations thus present FTLD-tau pathology and are likely to have the same clinical syndromes associated with sporadic FTLD-tau [108]. Given these strong associations between both etiologies, transgenic mouse models for the study of FTLD-tau rely on modeling the genetic forms caused by MAPT mutations.

More than 40 different MAPT mutations have been associated with FTDP-17T [109]. Most of them are missense mutations located in the microtubule-binding region or other regions of the protein. However, mutations in such other regions are thought to end structurally and functionally related to the microtubule-binding domain due to protein folding [110]. Tau mutations have been attributed to causing both loss-of-function and gain-of-function effects by reducing microtubule stabilization and increasing its aggregation and phosphorylation respectively [111, 112].

Detailed information on all models listed below can be found at The most important transgenic lines used for FTDP-17T modeling can be found in Table 3 (Ref. [113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134]). Transgenic mice devoid of tau expression resulted in no overt phenotype or malformations, although age-associated behavioral changes and subtle motor deficits have been identified in certain lines [135]. Nevertheless, these lines were fundamental to identifying tau functions (reviewed in [135]). On the other hand, transgenic mice expressing wild-type human tau also remain unaffected except for the Tg2652 transgenic line [113] in which human tau is greatly overexpressed producing widespread pretangle pathology at a young age, but the phenotype does not progress to mature neurofibrillary tangles or neuronal loss [113]. Behaviorally, these mice show deficits in muscle strength, as well as in spatial learning and memory [113]. The most useful models rely on the expression of human tau harboring MAPT mutations like P301S and P301L (Table 3). In human-mutated MAPT models, the expression of mutant tau was sufficient to cause tau aggregation in NFTs and neuronal death. Indeed, in certain models both processes could be dissociated, suggesting that soluble tau aggregates are responsible for neuronal death instead of the larger NFTs [114, 115, 116, 117]. Functional deficits like synaptic loss, behavioral changes, and cognitive impairment have also been reported in human mutated tau models and proved to be reversible in conditional transgenic lines [117, 118, 119, 136].

Table 3.Transgenic mouse models of frontotemporal dementia (FTDP-17T).
Gene Generation technique Name Promoter Construct Neuronal loss Tau protein deposition Clinical signs Reference
MAPT Transgeni-c-Microinjection JNPL3 Prnp MAPT (P301L) No Yes NFTs, gliosis, motor symptoms, behavioural symptoms [120]
rTg4510 CaMKIIα(Tet-off) MAPT (P301L) Yes Yes NFTs, memory deficits, cognitive impairment [115, 116, 121]
PS19 Prnp MAPT (P301S) Yes Yes NFTs, microglial activation, synaptic plasticity deficits [118]
Pro-Aggr CaMKIIα(Tet-off) MAPT (ΔK280) Yes Yes NFTs, astrogliosis [117, 119]
Missorting, phosphorylation, and aggregation of TauRD/ΔK280 protein are reversible after switching off the expression, only mouse Tau tangles tend to persist
Anti-Agrr CaMKIIα(Tet-off) MAPT (ΔK280, I277P, I308P) No No None (I227P and I308P mutations inhibit Tau aggregation in vitro and in cell models) [117]
pR5 Thy1.2 MAPT (P301L) Yes Yes Astrocytosis, NFTs [122]
hTau MAPT Genomic MAPT or cDNA MAPT No Yes Tau-immunoreactive axonal swellings and aggregation, hind-limb abnormality [114, 123, 124]
hTau-A152T CaMKIIα(Tet-off) MAPT (A152T) Yes Yes Abnormal accumulation of soluble Tau, learning and memory deficits [125]
hTau.P301S Thy-1 MAPT (P301S) Yes Yes NFTs, astrocytosis, motor deficits [126]
mThy-1 3R Tau Thy-1 MAPT (L266V, G272V) Yes Yes Pick-body type Tau aggregates, astrogliosis, mitochondrial patology, memory deficits, motor deficits, increased anxiety [127]
Tau4RTg2652 Thy1.2 MAPT No - Tau hyperphosphorylation, neuron dystrophy, motor deficits, cognitive deficits [113]
Transgenic-Knock in hTau-AT Thy1.2 MAPT (A152T) Yes Yes NFTs, learning and memory deficits [128, 129]
Transgenic-Knock out tau-/- mice Mapt Mapt interruption (neomycin) No No None at young age, subtle motor deficits at 1 year of age [130, 131]
TAU/ mice Mapt Mapt interruption (neomycin) No No None at young age, complex motor deficits at elder age, slower neuron maturation [132, 133]
tau knockout mice Mapt Mapt interruption (neomycin) No No None [134]
4. Transgenic Mouse Models for the Study of Alzheimer’s Disease

AD is the most prevalent form of dementia and contributes to 60–70% of all dementia cases [137]. Patients show progressive symptoms that firstly include deficits in short-term memory that led to later cognitive impairment and neuropsychiatric symptoms that severely disable patients to the extent of being unable normal life activities [138].

AD is mainly characterized by the presence in diseased brains of amyloid plaques composed of amyloid-β (Aβ) peptides derived from the processing of the amyloid precursor protein (APP) and NFTs composed of hyper-phosphorylated tau [139]. Such hallmarks were first reported in 1906 by German doctor Alois Alzheimer [140]. Apart from amyloid plaques and NFTs, AD brains are further characterized by synaptic and neuronal loss and reactive astrogliosis and microgliosis [141].

The discovery that amyloid plaques were composed of Aβ peptides pointed to Aβ as being the potential causal factor for AD. Aβ peptides are formed during the cleaving of the transmembrane APP protein by proteases BACE1 [142] and gamma-secretase complex, releasing peptides Aβ40 and Aβ42 to the extracellular space [143]. These peptides are extremely hydrophobic and prone to aggregate, forming insoluble fibrils which turn into plaques. Initially, Aβ deposits were thought to be neurotoxic and promote the formation of NFTs by a similar cascade of polymerization of phosphorylated tau molecules into progressively bigger and insoluble fibrils that end up forming NFTs [144, 145]. However, cumulative evidence showed that AD has a more complex and multifactorial pathogenesis, in which cognitive decline seems to be more linked to NFTs accumulation than to Aβ deposition [146]. In addition, it seems that soluble Aβ and tau oligomers that precede amyloid plaque and NFTs are the causative agents of synaptic damage and neuronal death [147, 148, 149].

More than 90% of AD cases are late-onset and of unknown etiology, which are known as sporadic AD cases (SAD) [150]. By contrast, the rest of the AD cases are caused by dominant autosomal inheritance of mutations in genes related to Aβ generation like APP, PSEN1, and PSEN2. These last two genes codify proteins acting in the gamma-secretase complex. The familial forms of AD (FAD) are early-onset and high penetrant. Transgenic mouse modeling FAD aimed to gain insights into molecular mechanisms that will later be applied to SAD cases. However, there is no single mouse model that completely recapitulates all pathological and behavioral phenotypes of AD. Indeed, wild-type rodents do not develop Aβ plaques or NFTs in normal conditions possibly because of their lifespan, which may not allow a long pre-symptomatic phase as happens in humans [151]. The most relevant transgenic mouse models generated to model AD will be discussed and their main advantages and caveats analyzed (Table 4, Ref. [144, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174]). It is important to note that before FAD modeling, models aimed to mimic the disruption in the cholinergic system in rodents by mechanical, electrical, or chemical lesions [175]. More detailed information about the AD transgenic mouse models available can be found at

Table 4.Transgenic mouse models of Alzheimer’s disease (AD).
Gene Generation technique Name Promoter Construct Neuronal loss Aβ deposition Clinical signs Reference
APP Transgenic-Microinjection A7 APP transgenic Thy1.2 APP (K670M, N671L, T714I) - Yes Optogenetic stimulation, induced epileptic seizures [154]
APP23 Thy 1 APP (K670M, N671L) Yes Yes Microglia activation, dystrophic neurites containing hyperphosphorylated Tau, memory deficits, hyperactivity [152]
APPDutch Thy 1 APP (E693Q) - Yes Aβ deposition in blood vessels, gliosis [155]
APP E693Δ-Tg (Osaka) Prnp APP (E693Δ) Yes Yes Aβ deposition, dystrophic neurites, abnormal Tau phosphorylation, gliosis, cognitive impairment [153]
APPSwe Thy1.2 APP (K670M, N671L) - Yes Aβ plaques [156]
J20 PDGF-β APP (K670M, N671L, V717F) Yes Yes Aβ plaques, dystrophic neurites, learning deficits, memory deficits, hiperactivity [157]
Tg2576 Prnp (hamster) APP (K670M, N671L) No Yes Aβ plaques, vascular amyloid, astrogliosis, microgliosis, cognitive impairment [158]
TgCRND8 Prnp (hamster) APP (K670M, N671L, V717F) Yes Yes Aβ plaques, activated microglia, dystrophic neurites, cognitive impairment, cholinergic dysfunction [159]
Transgenic-Knock in APP NL-F Knock-in App App (K670M, N671L, I716F) No Yes Aβ plaques, microgliosis, astrocytosis, synaptic loss, memory impairment [160]
APP NL-G-F Knock-in App App (K670M, N671L, I716F, E693G) No Yes Aβ plaques, microgliosis, astrocytosis, synaptic loss, memory impairment [160]
App knock-in (humanized Aβ) App APP No No None [161]
hAβ-KI App APP No No None [162]
Transgenic- Knock out APP-Deficient mice App App interruption (neomycin) No No Lower weight, decreased locomotor activity and forelimb grip strength, reactive gliosis at 14 weeks of age [144]
PSEN1 Transgenic-Microinjection PSEN1(WT) Nse PSEN1 No No None [163]
PS1(A246E) Thy 1 PSEN1 (A246E) No No None [165]
PS1(M146L) Pdgf-β (rat) PSEN1 (M146L) No No Disregulation of calcium homeostasis [166]
PS1(M146V) Pdgf-β (rat) PSEN1 (M146V) No No Disregulation of calcium homeostasis [166]
Transgenic-Knock in PS1(P264L) Psen1 Psen1 (P264L) No No None [167]
PSEN1(M146V) Knock-In Psen1 Psen1 (M146V) No No Disregulation of calcium homeostasis [168]
Transgenic-Knock out PS1 Null mice Psen 1 Psen 1 interruption (neomycin) Yes No Limited survival. Skeleton deformation, CNS hemorrhages, neurogenesis impairment, massive neuronal loss in specific subregions [164]
PSEN2 Transgenic-Microinjection NSE-hPS2(N141I) Nse PSEN2 (N141I) No No None [170]
PS2(N141I) Prnp PSEN2 (N141I) No No Disregulation of calcium homeostasis [156]
Transgenic-Knock out PS2-Deficient Mice Psen 2 Psen 2 interruption (hygromycin) No No Mild pulmonary fibrosis and pulmonary hemorrhage [169]
APP/PSEN1 Transgenic-Microinjection 5xFAD Thy 1 APP (K670M, N671L, I716V, V717I)/PSEN1 (M146V, L286V) Yes Yes Aβ plaques, gliosis, synaptic dysfunction, cognitive impairment, motor symptoms [170]
APPPS1 Thy 1 APP (K670M, N671L)/PSEN1 (L166P) No Yes Aβ plaques, gliosis, synaptic dysfunction, cognitive impairment [171]
APPPS1 Thy 1 APP (K670M, N671L)/PSEN1 (L166P) Yes Yes Aβ plaques, gliosis, synaptic dysfunction, cognitive impairment [172]
APP/PSEN2 PS2APP Thy1.2 (APP)/Prnp (PSEN2) APP (K670M, N671L)/PSEN2 (N141I) No Yes Aβ plaques, gliosis, synaptic dysfunction, cognitive impairment, dysregulation of calcium homeostasis [173]
APP/PSEN1/MAPT 3xTg Thy1.2 APP (K670M, N671L)/PSEN1 (M146V)/MAPT (P301L) Yes Yes Aβ plaques, NFTs, synaptic dysfunction, cognitive impairment [174]
4.1 Amyloid-Beta Precursor Protein (APP)

AD senile plaques are mainly composed of Aβ peptides that result from the proteolytic processing of the APP protein. The discovery of FAD linked to point mutations in the APP gene led to the development of many transgenic mouse models based on APP genetic modification (Table 4). Point mutations causative of FAD is mainly amino acid substitutions that received the names of the populations in which they were discovered (for instance, the E693Q or so-called Dutch mutation). Mutations in APP are also associated with cerebral amyloid angiopathy disease [176].

The disruption of the APP gene to generate KO mice resulted in animals that do not show physical symptoms, although some subtle phenotypes including behavioral deficits were described [177]. In the same line of results microinjected, knock-in, and CRISP/CAS9 transgenic mice produced to express wild-type human APP protein showed in general terms no neuropathology, behavior, or cognitive phenotypes although some subtle phenotypes were also reported (Table 4).

By contrast, the vast majority of models expressing the human APP gene harboring mutations related to FAD end developing amyloid plaques at different points of their lifespan as well as memory and cognitive deficits as measured by different performing tests like the Morris water maze test [138]. However, neuropathological findings were exclusive to Aβ deposits, even in cases in which more than one APP-FAD-linked mutation was introduced in the APP sequence. Some models presented abnormal tau phosphorylation as well [152, 153] but overt NFT pathology was not achieved.

4.2 Presenilin-1 (PSEN1)

PSEN1 encodes presenilin-1, one of the four subunits of the gamma-secretase complex responsible for Aβ generation. More than 300 mutations in PSEN1 have been reported, and mutations in PSEN1 are the most common cause of early-onset Alzheimer’s disease [163].

Inactivation of the PSEN1 gene led to negative phenotypes including impaired neurogenesis and neuron maturation, massive neuronal loss, brain hemorrhages, behavior deficits, and premature death as well as abnormalities in Aβ processing [178]. By contrast, expression of the human wild-type PSEN1 produced no pathological changes [163].

The introduction of FAD-linked mutations in the PSEN1 sequence did not produce overt Aβ deposition, although certain dysregulations in normal APP processing were detected (Table 4). Other detected phenotypes included altered mitochondrial activity, dysregulated calcium homeostasis, and increased sensitivity towards kainic acid in terms of seizures and neuronal damage. Irrespective of the mutation modeled, a proper AD phenotype was not achieved in PSEN1 transgenic mice.

4.3 Presenilin-2 (PSEN2)

The gene PSEN2 encodes presenilin-2, another subunit of the gamma-secretase complex involved in APP processing and Aβ generation. Missense mutations in PSEN2 are a rare cause of early-onset Alzheimer’s disease [178].

Disruption of the PSEN2 gene in transgenic mice did not produce brain, cognitive or behavioral abnormalities, although the function of the mice’s respiratory system was compromised [169]. Transgenic mice expressing the FAD-linked mutation N141I did also not present any AD-related histological finding, although behavioral deficits, alterations in normal APP processing, and impaired calcium homeostasis were reported (Table 4).

4.4 Combinatorial Models

Since transgenic mice for APP, PSEN1, and PSEN2 genes did not faithfully reproduce the AD phenotype, combinatorial models harboring mutations in more than one gene linked to FAD have been generated (Table 4). Mutations in the MAPT gene were also included in some of the models given that solid tau pathology was not achieved by solely altering APP processing involved genes. These models were produced either by crossing previously existing single-gene transgenic mice or by delivering the desired transgenes all at once.

In general terms, combinatorial models are more successful in reproducing certain FAD hallmarks (Table 4). Aβ deposits appear earlier, in more amounts, are better organized in amyloid plaques, and tend to extend more through different brain areas. In addition, amyloid plaques were even surrounded by dystrophic neurons and activated microglia and astrocytes. Neuronal loss was detected in some models. Tau pathology is also detected in that models in which the MAPT gene was also mutated, although in some models proper NFT formation was not achieved. FAD combinatorial models also show cognitive impairment that worsens with age and is mainly focused on memory tasks. Motor phenotypes were also reported in certain models.

Although combinatorial models produced invaluable insights into FAD-related mechanisms, it is important to note that they do not fully reproduce human AD phenotype. In addition, the combination of mutations in several genes, even with more than one mutation in one single gene which is used to generate the combinatorial models, does not exist in humans.

5. Transgenic Mouse Models for the Study of Huntington’s Disease

Huntington’s disease (HD) is an inherited ND mainly characterized by motor, psychiatric and cognitive impairments [179]. Unstable CAG repeat expansion in the huntingtin gene (HTT) is the cause of the disease, which codifies for a polyglutamine domain in the N-terminal part of the protein. HD is inherited in an autosomal dominant pattern. Healthy HTT alleles contain from 6 to 35 repeats of the CAG triplet in the (CAG)nCAACAG region of the HTT gene. A higher risk of disease development has been established from 36 to 39 repeats, while 40 or more repeats cause fully penetrant HD. The age of onset of motor symptoms negatively correlates with the CAG repeat number, the more repeats the sooner the symptoms appear. The main pathological hallmark of HD is the extended neuronal loss in the striatum and cerebral cortex areas as well as extensive brain atrophy [180].

Once the HTT gene was discovered in 1993 [181] a great variety of HD animal models have been produced including transgenic mice. These models have been of utility for unraveling the pathological mechanisms of the disease and for the evaluation of therapeutic interventions in preclinical studies (Table 5, Ref. [182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195]).

Table 5.Transgenic mouse models of Huntington’s disease (HD).
Gene Type of HD model Generation technique Name CAG repeat lenght Promoter Construct Striatum neuron loss Huntingtin protein deposition Clinical signs Reference
HTT N-terminal transgenic and fragment models Transgenic-Microinjection R6/1 116 HTT Exon 1 HTT containing genomic fragment Yes Yes Motor and cognitive impairment, failure to gain weight [183]
R6/2 116 HTT Exon 1 HTT containing genomic fragment Yes Yes Dossage effect on age of onset and phenotype severity [184]
128 Motor and cognitive impairment, failure to gain weight, deficits in synaptic plasticity, cardiac and skeletal muscle abnormalities
N171-82Q 82 Prnp First 171 amino acids HTT No Yes Motor and cognitive impairment, failure to gain weight [185]
Tg100 100 NSE (rat) First 3 kb of HTT cDNA No Yes Motor and cognitive impairment, abnormal dendritic morphology, failure to gain weight [186]
Transgenic fulllenght models Transgenic-Bacterial artificial chromosome BACHD 97 HTT Exon 1 HTT No Yes Motor and cognitive impairment, abnormal striatal morphology, weight gain [187]
Transgenic-Yeast artificial chromosome YAC128 125 HTT HTT Yes Yes Motor and cognitive impairment, weight gain [188]
Cross of BACHD and YAC18 mice Hu97/18 18 and 97 HTT Exon 1 HTT No Yes Motor and cognitive impairment, striatal atrophy, weight gain [189]
Cross of YAC128 and BAC21 mice Hu128/21 125 and 21 HTT Exon 1 HTT No Yes Motor and cognitive impairment, striatal atrophy, weight gain, testicular atrophy [190]
Transgenic-Knock in CAG140 146 Htt Chimeric HTT exon 1/Htt No Yes Mild motor and cognitive impairment [191]
zQ175 188 Htt No - Spontaneous expansion of the CAG copy number in CAG140 mice [192]
Motor and cognitive impairment, transcriptional dysfunction of striatal genes, failure to gain weight
HdhQ20 20 Htt Not analyzed Yes Inherited instability of CAG repeats by gametogenesis [193]
HdhQ50 50
HdhQ80 80
HdhQ92 92
HdhQ111 111
HdhQ50 50 Htt No Yes Dossage effect on age of onset and phenotype severity [194]
HdhQ100 100
HdhQ200 200
HdhQ250 250 Motor and cognitive impairment, reactive gliosis
HdhQ315 315
HdhQ365 365
HdhQ150 150 Htt No Yes Motor and cognitive impairment, transcriptional dysfunction of striatal and cerebellum genes, failure to gain weight [195]
Transgenic-Knock out R1ag5 L7ag13 - Htt Htt interruption (Cre-LoxP system) Yes Yes Progressive degenerative neuronal phenotype and sterility [182]

HTT gene ablation in mice results in early embryonic lethality. Thus, the normal function of huntingtin in adult mice relies on the Cre/loxP site-specific recombination strategy to produce conditional ablation, finally resulting in a progressive degenerative neuronal phenotype [182]. In contrast with the experience of other NDs, HTT transgenic mice do recapitulate human HD phenotype including brain HTT aggregates and inclusions, motor and cognitive impairment, synaptic plasticity deficits, electrophysiological alterations, and neuron loss (Table 5). Motor symptoms include tremors, hypokinesia, and lack of coordination. Interestingly, transgenic mice expressing only the mutant N-terminal part of the HTT gene codifying only for exon 1 develop the disease earlier and with more pronounced symptoms than transgenic mice expressing several copies of the full mutant HTT gene or knock-in mice [183, 184, 185, 186]. Despite this disadvantage of full-length HTT models, they are more suitable for the study of certain HTT therapeutic interventions like HTT lowering strategies [187, 188, 189, 190].

6. Transgenic Mouse Models for the Study of Prion Diseases

Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative diseases that affect humans and other mammal species, some of them included in the human food chain. Humans are affected by Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), and familial fatal insomnia (FFI). TSEs produce long incubation times and their main symptoms are neurological behavior abnormalities, but motor dysfunction, cognitive impairment, and cerebral ataxia can also appear. In individuals affected by a TSE the normal form of the prion protein, also known as cellular form or PrPC, is converted into a disease-associated form known as PrPSc [196]. PrPC transformation into PrPSc causes a change in the protein tridimensional structure characterized by an increase in the β-sheet content [197]. While PrPC is monomeric, soluble in nonionic detergents, and sensitive to protease action, PrPSc tends to aggregate, is not soluble in non-ionic detergents, and is partially resistant to proteases [198].

One of the main differences between prion diseases with the rest of NDs is that they have a wider range of different etiologies. They can be infectious, iatrogenic, sporadic, or genetic.

Infectious and iatrogenic prion diseases are caused by the entry of an external PrPSc source that starts transforming host PrPC into new, ascent PrPSc. Thus, variant CJD (vCJD) is an infectious TSE caused by the consumption of Bovine Spongiform Encephalopathy (BSE)-contaminated meat products while iatrogenic CJD, for example, may be caused by a cornea transplant from a CJD-infected donor [199]. In the particular case of infectious TSEs, certain prion agents can be transmitted from one species to a different one. This is known as interspecies prion transmission and is affected by the homology between the primary sequences of inoculum PrPSc and host PrPC [200]. Mismatches between sequences also influence TSE progression [200]. Thus, the study of prion transmission is of crucial importance from the point of view of human health and food safety. For that purpose, transgenic mouse lines expressing the prion protein from different species of interest would provide useful models for the study of how certain TSEs may jump from one species to another.

Genetic TSEs are due to mutations in the PRNP gene. In humans, approximately 10–15% of TSEs are genetic [201]. PRNP mutations are thought to spontaneously promote the misfolding of PrPC into PrPSc and/or stabilize the PrPSc molecules once formed [201]. There are three different human genetic prion diseases based on their clinical and pathological features: familial CJD (fCJD), GSS, and FFI [202]. fCJD is rapidly progressive dementia in which patients present cerebral spongiform degeneration. GSS is a slowly progressive disease in which patients show ataxia, few spongiform degeneration, and abundant PrPSc amyloid plaques. Finally, the principal FFI symptom is progressive insomnia that derives in hallucinations and dementia, as well as high spongiosis in the thalamus.

The prion protein amino acid sequence is well conserved throughout evolution in mammal species [202]. This fact suggests that the prion protein in its cellular form has an important function. However, KO mice for the PRNP gene were fully developed till the end of their lifespan without any obvious detriment phenotypes [203, 204]. Different functions were inferred for the prion protein, but there is controversy on which of these inferred functions are real and the role that the different genetic backgrounds of the animal models may have played in the observed phenotypes [205] like synaptic and electrophysiological deficits, hematopoietic stem cell renewal, circadian rhythm regulation, processing of sensory information in the olfactory system or neural stem cell proliferation in adult neurogenesis [203, 204]. However, the most important and validated effect of PRNP depletion is resistance to prion infection [203, 204, 206].

With a focus on human health, transgenic mice expressing human PrP have been developed to study genetic, sporadic, and infectious prion diseases (Table 6, Ref. [203, 204, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225]). Different human PrP transgenic lines have been produced and found susceptible to kuru and sCJD prions [208, 209, 210, 211, 226, 227]. Human PrP transgenic models are also useful for the study of human susceptibility to animal prion strains. To date, the only recognized zoonotic prion disease is vCJD which first appeared in the United Kingdom in 1996 [228] and was soon proved to be caused by BSE-contaminated meat consumption [229]. The M129V polymorphism of human PrP is of special importance for human prion susceptibility. All vCJD definitely diagnosed cases are homozygous for the methionine allele, except for one recently found heterozygous case [230]. Transgenic mouse lines overexpressing human PrP harboring the M129 allele (Table 6) are successfully infected with BSE prions with a high resistance as reflected in the long survival times and partial attack rates that animals present [211, 212, 227, 231]. These models mimic perfectly the real situation since virtually all of the UK population was exposed to BSE-contaminated meat, although just 232 cases of vCJD have been reported [232]. Transgenic mice overexpressing human PrP harboring the heterozygous M129V and homozygous V129 alleles (Table 2) have not been infected with BSE but vCJD transmission is successful, thus pointing to the risk that human to human secondary vCJD infection would pose for the population [233]. Sheep-passaged BSE can easier infect M129 human PrP transgenic mouse lines more when compared to cattle BSE [212, 234]. For other prions not proved to be zoonotic, animal bioassays using transgenic models showed certain zoonotic potential for several agents like cattle atypical BSE prions and small ruminant classical scrapie [209, 235, 236]. More studies are needed for other emerging strains like small ruminant atypical scrapie and cervid chronic wasting disease prions [237, 238]. In fact, chronic wasting disease prions have proved to have certain zoonotic potential [239].

Table 6.Transgenic mouse models of prion diseases.
Gene Prion disease Mutation PrP sequence Generation technique Name Spontaneous disease (onset) Neuropathology PrPres Transmissibility Reference
PRNP None Prnp interruption (neomycin) Mouse Transgenic-Knock out Zurich I No No No - [203]
Prnp interruption (neomycin) Mouse Npu No No No - [204]
Prnp interruption (TALEN-mediated genome editing) Mouse Zurich III No No No - [207]
None (Wt) Human V129 Transgenic-microinjection Tg152 No No No No [208]
Tg361 No No No No [209]
Transgenic-Knock in HuVTg No No No No [210]
Human M129 Transgenic-microinjection Tg440 No No No No [208]
Tg35 No No No No [211]
Tg340 No No No No [212]
Tg650 No No No No [213]
Transgenic-Knock in HuMTg No No No No [210]
fCJD E200K Human M129 Transgenic-microinjection Tg23 No No No - [214]
Bank vole I109 Tg7271 Yes (120 d) Yes Yes Yes [215]
D178N/V129 Mouse CJD-A21 Yes (150 d) Yes No No [216]
GSS P102L Mouse Tg174 Yes (200 d) Yes No Yes [217]
Tg87 Yes (150 d) Yes No Yes [218]
Tg2866 Yes (150 d) Yes No Yes [219]
Tg(GSS)22 Yes (160 d) Yes No Yes [220]
Cow 113LBoPrP-Tg037 Yes (190 d) Yes No Yes [221]
Human M129 Tg27 No No No - [217]
Mouse Transgenic-Knock in 101LL No No No - [222]
A117V Mouse MV128 Transgenic-microinjection Tg(A116V) Yes (150 d) Yes No - [223]
Human V129 Tg30 Yes (475 d) Yes No Yes [224]
FFI D178N/M129 Mouse FFI-26 Yes (200 d) Yes No No [225]
Bank vole I109 Tg15965 Yes (180 d) Yes Yes Yes [215]
PrPres, Proteinase K-resistant PrPSc; Wt, Wild-type; d, days.

Both for the study of the onset, progression, and molecular mechanisms involved in these diseases as well as for the test of possible treatments, transgenic mouse models of genetic TSEs would be of great usefulness. Something important to note is that practically all attempts to produce transgenic mouse models for human genetic TSEs using the human PrP sequence had been unsuccessful, except for one recent model for GSS [224]. The rest of the successful transgenic mouse models for genetic TSEs have been made in the mouse, bank vole, or cattle PrP sequences or chimeric mouse/human PrP molecules.

7. Concluding Remarks

Despite the huge efforts done by the scientific community, NDs do not have any effective treatment these days. Numerous models have been generated based on the assumption that modeling the genetic “simpler” versions of NDs will provide useful insights to be later applied to the more common sporadic NDs. Unfortunately, in many cases, the generated models do not even fully reproduce the human phenotypes. Usually, the pathological and behavioral phenotypes displayed by the mice are milder, especially regarding behavioral alterations and neuron loss even though they were created using the same causative mutations (reviewed by [240]). This suggests the possible existence of unknown compensatory mechanisms in mice that may explain late-onset disorders and provide targets for novel strategies designed to extend neuronal function and survival [241]. In addition, it is also possible that this genetic “simpler” version of NDs is not only caused by mutations. In this sense, environmental factors might be the key to producing more reliable models. For instance, a high fat diet suministered to a transgenic mouse model of AD generated early prediabetic hyperinsulinemia that exacerbate AD pathology [242]. Other interesting option to generate models might be to produce transgenic mice with enhanced neuroprotective abilities. An example of such an approach is the overexpression of TREM2 (gene encoding receptor expressed on myeloid cells 2) in Tau transgenic mice, who showed that higher levels of TREM2 prevented neuronal loss and attenuated Tau pathology [243].

The partially manifested phenotypes are usually “cured” by candidate drugs in preclinical trials, but this success does not translate to the following human clinical trials. For instance, the Tg2576 mice model for AD has been cured or their health has been improved by treatments evaluated in preclinical trials more than 300 times [244]. Therefore, projects aimed to “cure mice” by simply reducing the misfolded protein that is accumulating seem not to be working fine [245]. Indeed, it seems that misfolded protein accumulation in big aggregates is a protective mechanism given that shorter oligomers seem to be the most toxic species (reviewed in [148]).

Researchers from different NDs agree that although having a distinct molecular basis (in terms of the protein that gets misfolded and accumulated), behavioral phenotypes tend to overlap and the same happens at the molecular level regarding the pathways that led to cell death. Thus, a holistic and comprehensive approach aimed to unravel the neural death/survival circuits and their implication in different NDs may result in more successful candidates for the treatment of NDs. General pathways such as protein homeostasis, mitochondrial impairment, inflammation, oxidative stress, and cell death routes like apoptosis and autophagy are common to several NDs [246, 247]. Along the same line, the mentioned above mice modeling also environmental factors, with enhanced neuron survival as well as mice aimed to model all these general pathways will provide therapeutic targets not necessarily restricted to one ND. These newer models will probably be generated using the CRISPR-Cas9 system [4]. CRISPR systems are adaptable immune mechanisms used by bacteria to protect themselves from foreign nucleic acids. Their combination with the Cas9 nuclease and a guide RNA allows directing Cas9 to a specific target DNA site using standard RNA-DNA complementarity base pairing rules (reviewed in [4]). This results in facile, rapid, and efficient modification of endogenous genes in a wide variety of cell types and novel organisms that have traditionally been difficult to manipulate genetically. In addition, the CRISPR-Cas9 system avoids random integration in the host DNA typically obtained in classic transgenesis but it may cause off-target edition.

Despite the lack of success in generating treatment options, transgenic mouse models have undoubtedly extended our understanding of NDs in the past years. Those models that at least show the progressive nature of the disease may serve to decipher the molecular mechanisms that end up producing neurodegeneration, thus generating potential options for early diagnosis and treatment before the neurons are irrevocably lost. In this way, combining the information provided by the “genetic” models with that provided by future “pathway-focused” ones may provide opportunities to create new strategies for drug development. Even little progress may have a direct impact on the aged population healthcare given that the prevalence of neurodegenerative diseases is rapidly growing.

Author Contributions

All authors (AMM, SC, NFB, JCE, and JMT) have contributed to the conception and design of the manuscript. AMM has been involved in drafting the manuscript and all authors (AMM, SC, NFB, JCE, and JMT) have been involved in revising it critically for important intellectual content. All authors (AMM, SC, NFB, JCE, and JMT) give final approval of the version to be published. All authors (AMM, SC, NFB, JCE, and JMT) have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity.

Ethics Approval and Consent to Participate

Not applicable.


Not applicable.


This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2015; 11: 332–384.
Lees AJ, Tolosa E, Olanow CW. Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr. Movement Disorders. 2015; 30: 19–36.
Copeland NG, Jenkins NA, Court DL. Recombineering: a powerful new tool for mouse functional genomics. Nature Reviews Genetics. 2001; 2: 769–779.
Sander JD, Joung JK. CRISPR-Cas systems for editing, regulating and targeting genomes. Nature Biotechnology. 2014; 32: 347–355.
Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nature Reviews Disease Primers. 2017; 3: 17013.
Andlin-Sobocki P, Jönsson B, Wittchen H, Olesen J. Cost of disorders of the brain in Europe. European Journal of Neurology. 2005; 12: 1–27.
Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007; 68: 384–386.
Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson’s disease. Annual Review of Neuroscience. 2005; 28: 57–87.
Bartels AL, Leenders KL. Parkinson’s disease: the syndrome, the pathogenesis and pathophysiology. Cortex. 2009; 45: 915–921.
Halliday G, Lees A, Stern M. Milestones in Parkinson’s disease–clinical and pathologic features. Movement Disorders. 2011; 26: 1015–1021.
Weintraub D, Burn DJ. Parkinson’s disease: the quintessential neuropsychiatric disorder. Movement Disorders. 2011; 26: 1022–1031.
McCann H, Stevens CH, Cartwright H, Halliday GM. α-Synucleinopathy phenotypes. Parkinsonism & Related Disorders. 2014; 20: S62–S67.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997; 388: 839–840.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proceedings of the National Academy of Sciences of the United States of America. 1998; 95: 6469–6473.
Bengoa-Vergniory N, Roberts RF, Wade-Martins R, Alegre-Abarrategui J. Alpha-synuclein oligomers: a new hope. Acta Neuropathologica. 2017; 134: 819–838.
Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging. 2003; 24: 197–211.
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nature Medicine. 2008; 14: 504–506.
Li J, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nature Medicine. 2008; 14: 501–503.
Burke RE, Dauer WT, Vonsattel JPG. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Annals of Neurology. 2008; 64: 485–491.
Parkkinen L, O’Sullivan SS, Collins C, Petrie A, Holton JL, Revesz T, et al. Disentangling the relationship between lewy bodies and nigral neuronal loss in Parkinson’s disease. Journal of Parkinson’s Disease. 2011; 1: 277–286.
Gasser T, Hardy J, Mizuno Y. Milestones in PD genetics. Movement Disorders. 2011; 26: 1042–1048.
Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nature Genetics. 2014; 46: 989–993.
Bonifati V. Genetics of Parkinson’s disease–state of the art, 2013. Parkinsonism & Related Disorders. 2014; 20: S23–S28.
Gasser T. Mendelian forms of Parkinson’s disease. Biochimica Et Biophysica Acta. 2009; 1792: 587–596.
Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? The Lancet Neurology. 2009; 8: 382–397.
Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, et al. Missing pieces in the Parkinson’s disease puzzle. Nature Medicine. 2010; 16: 653–661.
Thomas B, Beal MF. Parkinson’s disease. Human Molecular Genetics. 2007; 16: R183–R194.
Valente EM, Arena G, Torosantucci L, Gelmetti V. Molecular pathways in sporadic PD. Parkinsonism & Related Disorders. 2012; 18: S71–S73.
Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. The Journal of Neuroscience. 2002; 22: 8797–8807.
Ninkina N, Connor-Robson N, Ustyugov AA, Tarasova TV, Shelkovnikova TA, Buchman VL. A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression. Scientific Reports. 2015; 5: 16615.
Roman AY, Limorenko G, Ustyugov AA, Tarasova TV, Lysikova EA, Buchman VL, et al. Generation of mouse lines with conditionally or constitutively inactivated Snca gene and Rosa26-stop-lacZ reporter located in cis on the mouse chromosome 6. Transgenic Research. 2017; 26: 301–307.
Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, et al. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Experimental Neurology. 2002; 175: 35–48.
Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, et al. Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 –> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99: 8968–8973.
Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. Journal of Neuroscience Research. 2002; 68: 568–578.
Li X, Patel JC, Wang J, Avshalumov MV, Nicholson C, Buxbaum JD, et al. Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S. The Journal of Neuroscience. 2010; 30: 1788–1797.
Ramonet D, Daher JPL, Lin BM, Stafa K, Kim J, Banerjee R, et al. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE. 2011; 6: e18568.
Tsika E, Kannan M, Foo CS, Dikeman D, Glauser L, Gellhaar S, et al. Conditional expression of Parkinson’s disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration. Neurobiology of Disease. 2014; 71: 345–358.
Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, et al. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nature Neuroscience. 2009; 12: 826–828.
Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, et al. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. The Journal of Biological Chemistry. 2005; 280: 21418–21426.
Chandran JS, Lin X, Zapata A, Höke A, Shimoji M, Moore SO, et al. Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function. Neurobiology of Disease. 2008; 29: 505–514.
Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron. 2005; 45: 489–496.
Rousseaux MWC, Marcogliese PC, Qu D, Hewitt SJ, Seang S, Kim RH, et al. Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 15918–15923.
Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, et al. DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104: 14807–14812.
Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102: 5215–5220.
Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken H, Becker D, et al. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE. 2009; 4: e5777.
Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104: 11441–11446.
Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. The Journal of Biological Chemistry. 2003; 278: 43628–43635.
Itier J, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, et al. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Human Molecular Genetics. 2003; 12: 2277–2291.
Rodríguez-Navarro JA, Casarejos MJ, Menéndez J, Solano RM, Rodal I, Gómez A, et al. Mortality, oxidative stress and tau accumulation during ageing in parkin null mice. Journal of Neurochemistry. 2007; 103: 98–114.
Oyama G, Yoshimi K, Natori S, Chikaoka Y, Ren Y, Funayama M, et al. Impaired in vivo dopamine release in parkin knockout mice. Brain Research. 2010; 1352: 214–222.
Kitada T, Tong Y, Gautier CA, Shen J. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. Journal of Neurochemistry. 2009; 111: 696–702.
Sanchez G, Varaschin RK, Büeler H, Marcogliese PC, Park DS, Trudeau L. Unaltered striatal dopamine release levels in young Parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice. PLoS ONE. 2014; 9: e94826.
Specht CG, Schoepfer R. Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neuroscience. 2001; 2: 11.
Hur E, Lee BD. LRRK2 at the Crossroad of Aging and Parkinson’s Disease. Genes. 2021; 12: 505.
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003; 299: 256–259.
Akundi RS, Huang Z, Eason J, Pandya JD, Zhi L, Cass WA, et al. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE. 2011; 6: e16038.
Glasl L, Kloos K, Giesert F, Roethig A, Di Benedetto B, Kühn R, et al. Pink1-deficiency in mice impairs gait, olfaction and serotonergic innervation of the olfactory bulb. Experimental Neurology. 2012; 235: 214–227.
Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102: 2174–2179.
Von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, et al. Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101: 10744–10749.
Tison F, Yekhlef F, Chrysostome V, Sourgen C. Prevalence of multiple system atrophy. Lancet. 2000; 355: 495–496.
Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). Journal of the Neurological Sciences. 1989; 94: 79–100.
Scherfler C, Puschban Z, Ghorayeb I, Goebel GP, Tison F, Jellinger K, et al. Complex motor disturbances in a sequential double lesion rat model of striatonigral degeneration (multiple system atrophy). Neuroscience. 2000; 99: 43–54.
Puschban Z, Stefanova N, Petersén A, Winkler C, Brundin P, Poewe W, et al. Evidence for dopaminergic re-innervation by embryonic allografts in an optimized rat model of the Parkinsonian variant of multiple system atrophy. Brain Research Bulletin. 2005; 68: 54–58.
Waldner R, Puschban Z, Scherfler C, Seppi K, Jellinger K, Poewe W, et al. No functional effects of embryonic neuronal grafts on motor deficits in a 3-nitropropionic acid rat model of advanced striatonigral degeneration (multiple system atrophy). Neuroscience. 2001; 102: 581–592.
Ghorayeb I, Fernagut PO, Hervier L, Labattu B, Bioulac B, Tison F. A ‘single toxin-double lesion’ rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis. Neuroscience. 2002; 115: 533–546.
Ghorayeb I, Fernagut PO, Aubert I, Bezard E, Poewe W, Wenning GK, et al. Toward a primate model of L-dopa-unresponsive parkinsonism mimicking striatonigral degeneration. Movement Disorders. 2000; 15: 531–536.
Ghorayeb I, Fernagut PO, Stefanova N, Wenning GK, Bioulac B, Tison F. Dystonia is predictive of subsequent altered dopaminergic responsiveness in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine+3-nitropropionic acid model of striatonigral degeneration in monkeys. Neuroscience Letters. 2002; 335: 34–38.
Fernagut PO, Diguet E, Stefanova N, Biran M, Wenning GK, Canioni P, et al. Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57Bl/6 mice: behavioural and histopathological characterisation. Neuroscience. 2002; 114: 1005–1017.
Fernagut P, Barraud Q, Bezard E, Ghorayeb I, Tison F. Metabolic activity of the subthalamic nucleus in a primate model of L-dopa-unresponsive parkinsonism. Neurological Research. 2010; 32: 1050–1053.
Fernagut P, Tison F. Animal models of multiple system atrophy. Neuroscience. 2012; 211: 77–82.
Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, et al. Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Reports. 2002; 3: 583–588.
Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, et al. Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. The American Journal of Pathology. 2005; 166: 869–876.
Boudes M, Uvin P, Pinto S, Voets T, Fowler CJ, Wenning GK, et al. Bladder dysfunction in a transgenic mouse model of multiple system atrophy. Movement Disorders. 2013; 28: 347–355.
Kuzdas D, Stemberger S, Gaburro S, Stefanova N, Singewald N, Wenning GK. Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: experimental evidence. Experimental Neurology. 2013; 247: 531–536.
Flabeau O, Meissner WG, Ozier A, Berger P, Tison F, Fernagut P. Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy. Movement Disorders. 2014; 29: 388–395.
Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, et al. Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. The Journal of Neuroscience. 2005; 25: 10689–10699.
Hoffmann A, Ettle B, Battis K, Reiprich S, Schlachetzki JCM, Masliah E, et al. Oligodendroglial α-synucleinopathy-driven neuroinflammation in multiple system atrophy. Brain Pathology. 2019; 29: 380–396.
Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, et al. Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005; 45: 847–859.
Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annual Review of Neuroscience. 2001; 24: 1121–1159.
Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, Mann DM, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathologica. 2011; 122: 137–153.
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathologica. 2014; 128: 755–766.
Boxer AL, Yu J, Golbe LI, Litvan I, Lang AE, Höglinger GU. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. The Lancet Neurology. 2017; 16: 552–563.
Irwin DJ, Brettschneider J, McMillan CT, Cooper F, Olm C, Arnold SE, et al. Deep clinical and neuropathological phenotyping of Pick disease. Annals of Neurology. 2016; 79: 272–287.
Rankin KP, Mayo MC, Seeley WW, Lee S, Rabinovici G, Gorno-Tempini ML, et al. Behavioral variant frontotemporal dementia with corticobasal degeneration pathology: phenotypic comparison to bvFTD with Pick’s disease. Journal of Molecular Neuroscience. 2011; 45: 594–608.
Dickson DW, Yen SH, Suzuki KI, Davies P, Garcia JH, Hirano A. Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathologica. 1986; 71: 216–223.
Braak H, Braak E. Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria. Journal of Neural Transmission. 1998; 105: 801–819.
Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013; 80: 496–503.
Day GS, Lim TS, Hassenstab J, Goate AM, Grant EA, Roe CM, et al. Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease. Neurology. 2017; 88: 1273–1281.
Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Movement Disorders. 2017; 32: 853–864.
Spinelli EG, Mandelli ML, Miller ZA, Santos-Santos MA, Wilson SM, Agosta F, et al. Typical and atypical pathology in primary progressive aphasia variants. Annals of Neurology. 2017; 81: 430–443.
Kovacs GG, Robinson JL, Xie SX, Lee EB, Grossman M, Wolk DA, et al. Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases. Journal of Neuropathology and Experimental Neurology. 2017; 76: 270–288.
Rodriguez RD, Suemoto CK, Molina M, Nascimento CF, Leite REP, de Lucena Ferretti-Rebustini RE, et al. Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study. Journal of Neuropathology and Experimental Neurology. 2016; 75: 628–635.
Arena JD, Smith DH, Lee EB, Gibbons GS, Irwin DJ, Robinson JL, et al. Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer’s disease. Brain. 2020; 143: 1572–1587.
Gigant B, Landrieu I, Fauquant C, Barbier P, Huvent I, Wieruszeski J, et al. Mechanism of Tau-promoted microtubule assembly as probed by NMR spectroscopy. Journal of the American Chemical Society. 2014; 136: 12615–12623.
Trinczek B, Ebneth A, Mandelkow EM, Mandelkow E. Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. Journal of Cell Science. 1999; 112: 2355–2367.
Hutton M. Molecular genetics of chromosome 17 tauopathies. Annals of the New York Academy of Sciences. 2000; 920: 63–73.
Wang Y, Mandelkow E. Tau in physiology and pathology. Nature Reviews Neuroscience. 2016; 17: 5–21.
Furman JL, Vaquer-Alicea J, White CL, Cairns NJ, Nelson PT, Diamond MI. Widespread tau seeding activity at early Braak stages. Acta Neuropathologica. 2017; 133: 91–100.
Jucker M, Walker LC. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nature Neuroscience. 2018; 21: 1341–1349.
Kuret J, Congdon EE, Li G, Yin H, Yu X, Zhong Q. Evaluating triggers and enhancers of tau fibrillization. Microscopy Research and Technique. 2005; 67: 141–155.
Mandelkow E, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor Perspectives in Medicine. 2012; 2: a006247.
von Bergen M, Barghorn S, Biernat J, Mandelkow E, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochimica Et Biophysica Acta. 2005; 1739: 158–166.
Sillen A, Leroy A, Wieruszeski J, Loyens A, Beauvillain J, Buée L, et al. Regions of tau implicated in the paired helical fragment core as defined by NMR. Chembiochem. 2005; 6: 1849–1856.
Pascual G, Wadia JS, Zhu X, Keogh E, Kükrer B, van Ameijde J, et al. Immunological memory to hyperphosphorylated tau in asymptomatic individuals. Acta Neuropathologica. 2017; 133: 767–783.
Guillozet-Bongaarts AL, Cahill ME, Cryns VL, Reynolds MR, Berry RW, Binder LI. Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. Journal of Neurochemistry. 2006; 97: 1005–1014.
Vana L, Kanaan NM, Ugwu IC, Wuu J, Mufson EJ, Binder LI. Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer’s disease. The American Journal of Pathology. 2011; 179: 2533–2550.
Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, et al. Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Archives of Neurology. 2005; 62: 925–930.
van Swieten J, Spillantini MG. Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathology. 2007; 17: 63–73.
Repository of variants in genes linked to Alzheimer’s disease. 2022. Available at: (Accessed: 1 June 2022).
Jeganathan S, von Bergen M, Brutlach H, Steinhoff H, Mandelkow E. Global hairpin folding of tau in solution. Biochemistry. 2006; 45: 2283–2293.
Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Human Mutation. 2004; 24: 277–295.
Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochimica Et Biophysica Acta. 2005; 1739: 240–250.
Wheeler JM, McMillan PJ, Hawk M, Iba M, Robinson L, Xu GJ, et al. High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration. Acta Neuropathologica Communications. 2015; 3: 33.
Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. The Journal of Neuroscience. 2005; 25: 5446–5454.
Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, et al. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. The American Journal of Pathology. 2006; 168: 1598–1607.
de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, et al. Caspase activation precedes and leads to tangles. Nature. 2010; 464: 1201–1204.
Mocanu M, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, et al. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. The Journal of Neuroscience. 2008; 28: 737–748.
Yoshiyama Y, Higuchi M, Zhang B, Huang S, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007; 53: 337–351.
Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. The Journal of Neuroscience. 2011; 31: 2511–2525.
Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genetics. 2000; 25: 402–405.
Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). The Journal of Neuroscience. 2005; 25: 10637–10647.
Götz J, Chen F, Barmettler R, Nitsch RM. Tau filament formation in transgenic mice expressing P301L tau. The Journal of Biological Chemistry. 2001; 276: 529–534.
Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, et al. Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiology of Disease. 2000; 7: 87–98.
Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde Y, et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. Journal of Neurochemistry. 2003; 86: 582–590.
Maeda S, Djukic B, Taneja P, Yu G, Lo I, Davis A, et al. Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. EMBO Reports. 2016; 17: 530–551.
Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. The Journal of Neuroscience. 2002; 22: 9340–9351.
Rockenstein E, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, et al. A novel triple repeat mutant tau transgenic model that mimics aspects of pick’s disease and fronto-temporal tauopathies. PLoS ONE. 2015; 10: e0121570.
Decker JM, Krüger L, Sydow A, Dennissen FJ, Siskova Z, Mandelkow E, et al. The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity. EMBO Reports. 2016; 17: 552–569.
Sydow A, Hochgräfe K, Könen S, Cadinu D, Matenia D, Petrova O, et al. Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD. Acta Neuropathologica Communications. 2016; 4: 17.
Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994; 369: 488–491.
Ikegami S, Harada A, Hirokawa N. Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neuroscience Letters. 2000; 279: 129–132.
Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. Journal of Cell Science. 2001; 114: 1179–1187.
Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nature Medicine. 2012; 18: 291–295.
Fujio K, Sato M, Uemura T, Sato T, Sato-Harada R, Harada A. 14-3-3 proteins and protein phosphatases are not reduced in tau-deficient mice. Neuroreport. 2007; 18: 1049–1052.
Ke YD, Suchowerska AK, van der Hoven J, De Silva DM, Wu CW, van Eersel J, et al. Lessons from tau-deficient mice. International Journal of Alzheimer’s Disease. 2012; 2012: 873270.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005; 309: 476–481.
Dementia’s Fact Sheet of WHO. 2022. Available at: (Accessed: 1 June 2022).
Götz J, Bodea L, Goedert M. Rodent models for Alzheimer disease. Nature Reviews Neuroscience. 2018; 19: 583–598.
Polanco JC, Li C, Bodea L, Martinez-Marmol R, Meunier FA, Götz J. Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies. Nature Reviews Neurology. 2018; 14: 22–39.
Hippius H, Neundörfer G. The discovery of Alzheimer’s disease. Dialogues in Clinical Neuroscience. 2003; 5: 101–108.
Duyckaerts C, Delatour B, Potier M. Classification and basic pathology of Alzheimer disease. Acta Neuropathologica. 2009; 118: 5–36.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286: 735–741.
Koo EH. The beta-amyloid precursor protein (APP) and Alzheimer’s disease: does the tail wag the dog? Traffic. 2002; 3: 763–770.
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends in Pharmacological Sciences. 1991; 12: 383–388.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992; 256: 184–185.
Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ. Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Frontiers in Genetics. 2014; 5: 88.
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Molecular Medicine. 2016; 8: 595–608.
Sengupta U, Nilson AN, Kayed R. The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMedicine. 2016; 6: 42–49.
Tracy TE, Gan L. Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease. Current Opinion in Neurobiology. 2018; 51: 134–138.
Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & Dementia. 2016; 12: 733–748.
Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. The New England Journal of Medicine. 2012; 367: 795–804.
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proceedings of the National Academy of Sciences of the United States of America. 1997; 94: 13287–13292.
Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, et al. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. The Journal of Neuroscience. 2010; 30: 4845–4856.
Yamada K, Yabuki C, Seubert P, Schenk D, Hori Y, Ohtsuki S, et al. Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. The Journal of Neuroscience. 2009; 29: 11393–11398.
Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, et al. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nature Neuroscience. 2004; 7: 954–960.
Richards JG, Higgins GA, Ouagazzal A, Ozmen L, Kew JNC, Bohrmann B, et al. PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. The Journal of Neuroscience. 2003; 23: 8989–9003.
Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. The Journal of Neuroscience. 2000; 20: 4050–4058.
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996; 274: 99–102.
Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, et al. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. The Journal of Biological Chemistry. 2001; 276: 21562–21570.
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al. Single App knock-in mouse models of Alzheimer’s disease. Nature Neuroscience. 2014; 17: 661–663.
Serneels L, T’Syen D, Perez-Benito L, Theys T, Holt MG, De Strooper B. Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease. Molecular Neurodegeneration. 2020; 15: 60.
Baglietto-Vargas D, Forner S, Cai L, Martini AC, Trujillo-Estrada L, Swarup V, et al. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology. Nature Communications. 2021; 12: 2421.
Wen PH, Shao X, Shao Z, Hof PR, Wisniewski T, Kelley K, et al. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiology of Disease. 2002; 10: 8–19.
Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997; 89: 629–639.
Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, et al. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. The Journal of Biological Chemistry. 2001; 276: 11539–11544.
Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996; 383: 710–713.
Siman R, Reaume AG, Savage MJ, Trusko S, Lin YG, Scott RW, et al. Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. The Journal of Neuroscience. 2000; 20: 8717–8726.
Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nature Medicine. 1999; 5: 101–106.
Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proceedings of the National Academy of Sciences of the United States of America. 1999; 96: 11872–11877.
Hwang DY, Chae KR, Kang TS, Hwang JH, Lim CH, Kang HK, et al. Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease. FASEB Journal. 2002; 16: 805–813.
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. The Journal of Neuroscience. 2006; 26: 10129–10140.
Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Reports. 2006; 7: 940–946.
Ozmen L, Albientz A, Czech C, Jacobsen H. Expression of transgenic APP mRNA is the key determinant for beta-amyloid deposition in PS2APP transgenic mice. Neuro-degenerative Diseases. 2009; 6: 29–36.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003; 39: 409–421.
Dodart J, May P. Overview on rodent models of Alzheimer’s disease. Current Protocols in Neuroscience. 2005; 33: 9.22.1-9.22.16.
Jäkel L, Van Nostrand WE, Nicoll JAR, Werring DJ, Verbeek MM. Animal models of cerebral amyloid angiopathy. Clinical Science. 2017; 131: 2469–2488.
Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, et al. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995; 81: 525–531.
Ayodele T, Rogaeva E, Kurup JT, Beecham G, Reitz C. Early-Onset Alzheimer’s Disease: What Is Missing in Research? Current Neurology and Neuroscience Reports. 2021; 21: 4.
Bates G, Tabrizi S, Jones L. Huntington’s disease. Oxford University Press: Oxford. 2014.
Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP. Neuropathological classification of Huntington’s disease. Journal of Neuropathology and Experimental Neurology. 1985; 44: 559–577.
MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons-disease chromosomes. Cell. 1993; 72: 971–983.
Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nature Genetics. 2000; 26: 300–306.
Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997; 90: 537–548.
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996; 87: 493–506.
Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Human Molecular Genetics. 1999; 8: 397–407.
Laforet GA, Sapp E, Chase K, McIntyre C, Boyce FM, Campbell M, et al. Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. The Journal of Neuroscience. 2001; 21: 9112–9123.
Gray M, Shirasaki DI, Cepeda C, André VM, Wilburn B, Lu X, et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. The Journal of Neuroscience. 2008; 28: 6182–6195.
Van Raamsdonk JM, Metzler M, Slow E, Pearson J, Schwab C, Carroll J, et al. Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiology of Disease. 2007; 26: 189–200.
Southwell AL, Warby SC, Carroll JB, Doty CN, Skotte NH, Zhang W, et al. A fully humanized transgenic mouse model of Huntington disease. Human Molecular Genetics. 2013; 22: 18–34.
Southwell AL, Skotte NH, Villanueva EB, Østergaard ME, Gu X, Kordasiewicz HB, et al. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles. Human Molecular Genetics. 2017; 26: 1115–1132.
Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet M. Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. The Journal of Comparative Neurology. 2003; 465: 11–26.
Menalled LB, Kudwa AE, Miller S, Fitzpatrick J, Watson-Johnson J, Keating N, et al. Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS ONE. 2012; 7: e49838.
Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, et al. Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Human Molecular Genetics. 1999; 8: 115–122.
Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, et al. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Human Molecular Genetics. 2001; 10: 137–144.
Woodman B, Butler R, Landles C, Lupton MK, Tse J, Hockly E, et al. The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Research Bulletin. 2007; 72: 83–97.
Prusiner SB. Molecular biology of prion diseases. Science. 1991; 252: 1515–1522.
Vázquez-Fernández E, Vos MR, Afanasyev P, Cebey L, Sevillano AM, Vidal E, et al. The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. PLoS Pathogens. 2016; 12: e1005835.
Prusiner SB. Prions. Proceedings of the National Academy of Sciences of the United States of America. 1998; 95: 13363–13383.
Hammersmith KM, Cohen EJ, Rapuano CJ, Laibson PR. Creutzfeldt-Jakob disease following corneal transplantation. Cornea. 2004; 23: 406–408.
Béringue V, Vilotte J, Laude H. Prion agent diversity and species barrier. Veterinary Research. 2008; 39: 47.
Watts JC, Prusiner SB. Experimental Models of Inherited PrP Prion Diseases. Cold Spring Harbor Perspectives in Medicine. 2017; 7: a027151.
Pastore A, Zagari A. A structural overview of the vertebrate prion proteins. Prion. 2007; 1: 185–197.
Büeler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. 1992; 356: 577–582.
Manson JC, Clarke AR, Hooper ML, Aitchison L, McConnell I, Hope J. 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Molecular Neurobiology. 1994; 8: 121–127.
Steele AD, Lindquist S, Aguzzi A. The prion protein knockout mouse: a phenotype under challenge. Prion. 2007; 1: 83–93.
Prusiner SB, Groth D, Serban A, Koehler R, Foster D, Torchia M, et al. Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proceedings of the National Academy of Sciences of the United States of America. 1993; 90: 10608–10612.
Nuvolone M, Sorce S, Paolucci M, Aguzzi A. Extended characterization of the novel co-isogenic C57BL/6J Prnp-/- mouse line. Amyloid. 2017; 24: 36–37.
Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell. 1995; 83: 79–90.
Cassard H, Torres J, Lacroux C, Douet J, Benestad SL, Lantier F, et al. Evidence for zoonotic potential of ovine scrapie prions. Nature Communications. 2014; 5: 5821.
Bishop MT, Hart P, Aitchison L, Baybutt HN, Plinston C, Thomson V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. The Lancet Neurology. 2006; 5: 393–398.
Asante EA, Linehan JM, Desbruslais M, Joiner S, Gowland I, Wood AL, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. The EMBO Journal. 2002; 21: 6358–6366.
Padilla D, Béringue V, Espinosa JC, Andreoletti O, Jaumain E, Reine F, et al. Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathogens. 2011; 7: e1001319.
Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, Perret-Liaudet A, et al. Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD. PLoS ONE. 2008; 3: e1419.
Asante EA, Gowland I, Grimshaw A, Linehan JM, Smidak M, Houghton R, et al. Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins. The Journal of General Virology. 2009; 90: 546–558.
Watts JC, Giles K, Bourkas MEC, Patel S, Oehler A, Gavidia M, et al. Towards authentic transgenic mouse models of heritable PrP prion diseases. Acta Neuropathologica. 2016; 132: 593–610.
Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, et al. Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model. Neuron. 2008; 60: 598–609.
Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ, Prusiner SB. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science. 1990; 250: 1587–1590.
Hsiao KK, Groth D, Scott M, Yang SL, Serban H, Rapp D, et al. Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 9126–9130.
Telling GC, Haga T, Torchia M, Tremblay P, DeArmond SJ, Prusiner SB. Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes & Development. 1996; 10: 1736–1750.
Nazor KE, Kuhn F, Seward T, Green M, Zwald D, Pürro M, et al. Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice. The EMBO Journal. 2005; 24: 2472–2480.
Torres J, Castilla J, Pintado B, Gutiérrez-Adan A, Andréoletti O, Aguilar-Calvo P, et al. Spontaneous generation of infectious prion disease in transgenic mice. Emerging Infectious Diseases. 2013; 19: 1938–1947.
Manson JC, Jamieson E, Baybutt H, Tuzi NL, Barron R, McConnell I, et al. A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. The EMBO Journal. 1999; 18: 6855–6864.
Yang W, Cook J, Rassbach B, Lemus A, DeArmond SJ, Mastrianni JA. A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP. The Journal of Neuroscience. 2009; 29: 10072–10080.
Asante EA, Linehan JM, Tomlinson A, Jakubcova T, Hamdan S, Grimshaw A, et al. Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS. PLoS Biology. 2020; 18: e3000725.
Bouybayoune I, Mantovani S, Del Gallo F, Bertani I, Restelli E, Comerio L, et al. Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease. PLoS Pathogens. 2015; 11: e1004796.
Kong Q, Huang S, Zou W, Vanegas D, Wang M, Wu D, et al. Chronic wasting disease of elk: transmissibility to humans examined by transgenic mouse models. The Journal of Neuroscience. 2005; 25: 7944–7949.
Telling GC, Scott M, Hsiao KK, Foster D, Yang SL, Torchia M, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 9936–9940.
Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature. 1996; 383: 685–690.
Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J, et al. The same prion strain causes vCJD and BSE. Nature. 1997; 389: 448–450.
Mok T, Jaunmuktane Z, Joiner S, Campbell T, Morgan C, Wakerley B, et al. Variant Creutzfeldt-Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129. The New England Journal of Medicine. 2017; 376: 292–294.
Kong Q, Zheng M, Casalone C, Qing L, Huang S, Chakraborty B, et al. Evaluation of the human transmission risk of an atypical bovine spongiform encephalopathy prion strain. Journal of Virology. 2008; 82: 3697–3701.
Creutzfeldt-Jakob Disease International Surveillance Network. Year. Available at: http://www. (Accessed: 1 June 2022).
Fernández-Borges N, Espinosa JC, Marín-Moreno A, Aguilar-Calvo P, Asante EA, Kitamoto T, et al. Protective Effect of Val_129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease. Emerging Infectious Diseases. 2017; 23: 1522–1530.
Plinston C, Hart P, Chong A, Hunter N, Foster J, Piccardo P, et al. Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy infection following passage in sheep. Journal of Virology. 2011; 85: 1174–1181.
Béringue V, Herzog L, Reine F, Le Dur A, Casalone C, Vilotte J, et al. Transmission of atypical bovine prions to mice transgenic for human prion protein. Emerging Infectious Diseases. 2008; 14: 1898–1901.
Marín-Moreno A, Huor A, Espinosa JC, Douet JY, Aguilar-Calvo P, Aron N, et al. Radical Change in Zoonotic Abilities of Atypical BSE Prion Strains as Evidenced by Crossing of Sheep Species Barrier in Transgenic Mice. Emerging Infectious Diseases. 2020; 26: 1130–1139.
Wadsworth JDF, Joiner S, Linehan JM, Balkema-Buschmann A, Spiropoulos J, Simmons MM, et al. Atypical scrapie prions from sheep and lack of disease in transgenic mice overexpressing human prion protein. Emerging Infectious Diseases. 2013; 19: 1731–1739.
Wadsworth JDF, Joiner S, Linehan JM, Jack K, Al-Doujaily H, Costa H, et al. Humanized Transgenic Mice Are Resistant to Chronic Wasting Disease Prions From Norwegian Reindeer and Moose. The Journal of Infectious Diseases. 2022; 226: 933–937.
Hannaoui S, Zemlyankina I, Chang SC, Arifin MI, Béringue V, McKenzie D, et al. Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD. Acta Neuropathologica. 2022; 144: 767–784.
Blesa J, Przedborski S. Parkinson’s disease: animal models and dopaminergic cell vulnerability. Frontiers in Neuroanatomy. 2014; 8: 155.
Kreiner G. Compensatory mechanisms in genetic models of neurodegeneration: are the mice better than humans? Frontiers in Cellular Neuroscience. 2015; 9: 56.
Ramos-Rodriguez JJ, Spires-Jones T, Pooler AM, Lechuga-Sancho AM, Bacskai BJ, Garcia-Alloza M. Progressive Neuronal Pathology and Synaptic Loss Induced by Prediabetes and Type 2 Diabetes in a Mouse Model of Alzheimer’s Disease. Molecular Neurobiology. 2017; 54: 3428–3438.
Jiang T, Zhang Y, Chen Q, Gao Q, Zhu X, Zhou J, et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology. 2016; 105: 196–206.
Zahs KR, Ashe KH. ‘Too much good news’ - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease? Trends in Neurosciences. 2010; 33: 381–389.
Franco R, Cedazo-Minguez A. Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans? Frontiers in Pharmacology. 2014; 5: 146.
Ramanan VK, Saykin AJ. Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. American Journal of Neurodegenerative Disease. 2013; 2: 145–175.
Scott L, Dawson VL, Dawson TM. Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson’s disease genes. Experimental Neurology. 2017; 298: 191–201.

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