Academic Editor: Rafael Franco
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Individuals
affected by the disease gradually lose their capacity for abstract thinking, understanding, communication and memory. As populations age, declining cognitive
abilities will represent an increasing global health concern. While AD was first
described over a century ago, its pathogenesis remains to be fully elucidated. It
is believed that cognitive decline in AD is caused by a progressive loss of
neurons and synapses that lead to reduced neural plasticity. AD is a
multifactorial disease affected by genetic and environmental factors. The
molecular hallmarks of AD include formation of
extracellular
Here we review the influence of infectious agents on the development of AD to inspire new research in dementia based on these pathogens.
In recent years, the steady aging of populations in predominantly developed countries has surfaced as both a success of modern medicine and an impending challenge for health care systems. The latter is associated with an increasing number of disorders characteristic for old age, including various degrees of cognitive impairment and dementia [1]. Epidemiologic studies have shown that dementia occurs relatively often in the general population and that its incidence is age-dependent. The frequency of dementia climbs from 1–10% in adults over 65 years old to 20–25% in those over 80 years old [2], and may be seen in as many as 30–40% of nonagenarians [3]. It has been projected that by the year 2040, the number of people affected by dementia will exceed 80 million [4] and could possibly grow to a staggering 130 million halfway through the 21st century [1]. Dementia drastically reduces quality of life by causing progressive decline of cognitive and executive functions including memory, attention, orientation, language, praxis, and visuospatial functions, and may lead to changes in behavior such as negative affect or a reversal of the sleep-wake cycle. Advancing disease makes patients suffering from dementia highly dependent on their caregivers [5, 6], a reality which has become particularly appreciable in the wake of the coronavirus disease 2019 (COVID-19) pandemic.
Neurodegenerative processes may be listed among the most common causes of
cognitive impairment. Alzheimer’s disease (AD) is the most common cause of
dementia, accounting for nearly half of the cases reported worldwide. There are
two major hallmarks of AD which play a crucial role in the pathophysiology of the
disease: the extracellular accumulation of the amyloid-beta peptide (A
In light of the multifactorial nature of AD, latent infections should not be discounted among the external factors potentially playing a role in its pathogenesis. Recent reports have provided data suggesting that certain microorganisms such as viruses, bacteria and unicellular parasites may be associated with cognitive decline. Microbes may either induce formation of AD-like pathology in the brain or acting indirectly, over-stimulate the immune system leading to an excessive inflammatory response such that may fuel certain neurodegenerative changes [12]. Examining the role of infectious agents and the inflammatory response associated with them in the context of AD might facilitate earlier diagnosis and lead to the identification of novel targets for treatment [3, 12].
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, may result in asymptomatic infection in about 15% of the individuals who contract it [13] and precipitate life-threatening disease in others. While acute respiratory symptoms typify the infection and have garnered a preponderance of the clinical and research attention directed at combatting the pandemic, neurological symptoms have been reported in approximately 30% of patients hospitalized for COVID-19 and may represent the initial manifestation of the disease [14, 15]. Numerous neurological manifestations ranging from headache, anosmia, and dysgeusia to more serious conditions including corticospinal tract signs, Guillain-Barré syndrome, ischemic stroke, encephalopathy, and meningoencephalitis have been reported [14, 16]. The potential impacts of SARS-CoV-2 on neurodegenerative diseases have also been considered. The most common of these, Alzheimer’s disease (AD) is the leading cause of dementia and may be particularly vulnerable to the effects of SARS-CoV-2 by virtue of the fact that a dysregulated renin-angiotensin system (RAS) is implicated in both conditions.
SARS-CoV-2 infectivity is predicated upon the virus exploiting
angiotensin-converting enzyme 2 (ACE2) to gain entry into host cells. While
necessary, however, ACE2 is not sufficient for this process to occur in all cells
[14, 17]. The transmembrane serine protease 2 (TMPRSS2) must first prime the
SARS-CoV-2 spike glycoprotein (S-protein) to allow for its association with the
Ser19-Asp615 extracellular region on ACE2 [14]. Several lines of evidence point
to this route of viral internalization having a particular bearing on AD.
Firstly, ACE2 was found to be upregulated five-fold in tissue autopsied from AD
patients versus controls [18]. Although this heightened expression can occur
secondary to the treatment of AD with ACE inhibitors or angiotensin
receptor blockers (ARBs) [14], ACE2 might serve a protective function given that
decreased levels of the enzyme were found to associate with increased A
Other factors beyond the RAS also likely contribute to effects of SARS-CoV-2 on
the CNS and AD risk. A recent interactome identified that the coronavirus
S-protein binds the alpha-secretase a disintegrin and metalloproteinase-9
(ADAM-9), which is thought to exert a protective effect against AD [14, 23],
however, whether the said interaction has clinical bearing remains to be
determined. Further, the APOE ε4-allele, a known risk factor for
late-onset AD, was recently correlated with an increased risk of severe COVID-19
infection [24], however this relationship might be confounded by ACE2 expression
level [25]. Astrocytic ApoE4 was recently found to promote
cholesterol delivery to neurons, driving lipid raft formation and potentiating
development of A
Pathogen | Influence on cognitive functions | Reference |
SARS-CoV-2 | Increased risk of cognitive impairment | [25, 29, 30] |
Potentially increased risk of AD | ||
HSV-1 | Increased risk of AD | [31] |
HSV-2 | Increased risk of cognitive impairment | [32] |
VZV | Increased risk of AD | [33] |
EBV | Potentially increased risk of AD | [34] |
CMV | Increased risk of cognitive impairment | [35] |
HHV-6 | Increased risk of AD | [34] |
HCV | Increased risk of cognitive impairment | [36] |
H5N1 | Increased risk of AD | [37] |
CA/09 H1N1 | Increased risk of AD | [38] |
Borrelia burgdorferi | Increased risk of AD | [39, 40] |
Treponema pallidum | Increased risk of dementia | [41] |
Chlamydia pneumoniae | Increased risk of AD | [42] |
Bacteria causing periodontitis* | Increased risk of cognitive impairment | [43] |
Propionibacterium acnes | Increased risk of AD | [44] |
Helicobacter pylori | Increased risk of dementia | [45] |
Toxoplasma gondii | Increased risk of AD | [46] |
*Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, Fusobacterium nucleatum, Aggregatibacter actinomycetemcmitans, Eikenella corrodens and Treponema denticola; HSV1, Herpes Simplex virus 1; HSV2, Herpes Simplex virus 2; HHV6, human betaherpesvirus 6; CMV, human cytomegalovirus; EBV, Epstein-Barr virus; H5N1, influenza virus strain H5N1; CA/09 H1N1, influenza virus strain H1N1. |
While evidence for an association between COVID-19 and AD pathogenesis exists, the capacity of SARS-CoV-2 to invade neurons remains contested. While mRNA expression might not correlate well with protein expression, both ACE2 and TMPRSS2 are considered to be poorly expressed in the CNS [14]. However, their expression may increase in the brain via the circulatory system or the nasal cavity via the olfactory nerve, which may explain the loss of smell in the course of COVID-19 infection [15]. Moreover, it is suggesting that SARS-CoV-2 might use other host proteins as vehicles for entry. Neuropilin 1 (NRP1), while neither sufficient nor necessary, potentiated SARS-CoV-2 entry into human embryonic kidney (HEK-293T) cells [17]. Notably, the rich expression of NRP1 in pulmonary and olfactory tissues [17] accords with the known tropism of the virus. The serine exopeptidase dipeptidylpeptidase 4 (DPP4), also known as cluster of differentiation 26 (CD26), has also come under scrutiny as a potential target of SARS-CoV-2, which too might be implicated in AD. Associated most commonly with the breakdown of incretins, DPP4 was found to be the cellular portal of entry for the Middle Eastern respiratory syndrome coronavirus (MERS-CoV) [47]. Bioinformatics analyses have revealed that while the S-protein of SARS-CoV-2 has a decreased affinity for DPP4 as compared with MERS-CoV, the former coronavirus is unique in being able to bind both ACE2 and DPP4 with appreciable strength [48]. Expressed predominantly in innate lymphoid cells, naïve CD4+ and CD8+ T cells, and plasmacytoid dendritic cells [49], DPP4 might not seem like an obvious factor linking COVID-19 and AD, however, several reports have identified that DPP4 inhibitors, commonly used in the treatment of type 2 diabetes mellitus, might also have utility in the treatment of neurodegenerative conditions [50, 51]. This utility might stem from the effects of DPP4 inhibitors on glucose metabolism, but also likely derives out of their anti-inflammatory and anti-fibrotic actions, which would be expected to alleviate the course of COVID-19 [52].
Further, age-related impairment of the blood-brain barrier (BBB), combined with an inflammation-induced reduction of BBB integrity such that may be seen in the context of AD [53] might render the CNS more susceptible to SARS-CoV-2 neuroinvasion. At the same time, SARS-CoV-2 causes endothelial dysfunction and enhances vascular permeability which may compromise BBB function [25]. Although viral entry into the CNS has been stipulated to occur by both hematogenous spread and ascension along olfactory fibers via synaptic transmission [25], the predominating route is not known. While earlier autopsy studies aimed at confirming the presence of SARS-CoV-2 in neural tissue via qRT-PCR and immunohistochemistry yielded equivocal results [54], more recent work has identified viral proteins in cortical neurons [55] as well as cranial nerves and cells within the brainstem [56]. Moreover, experiments conducted on organoids comprised of forkhead box protein G1 (FOXG1), paired box protein Pax-6 (PAX6), and B-cell lymphoma/leukemia 11B (CTIP2)-expressing dorsal cortical neurons and mice overexpressing human ACE2 have provided in vitro and in vivo evidence, respectively, of the neuroinvasive capacity of SARS-CoV-2 [55]. Nonetheless, analyses on the former showed no correlation between virus-infected cells and expression of ACE2, TMPRSS2, or NRP1 [55]. Indeed, many of the neurological manifestations of SARS-CoV-2 infection might stem not from direct viral invasion but from autoimmune processes secondary to the body’s generation of antibodies against viral particles [15]. That autopsy reports did not identify lymphocytosis in SARS-CoV-2-positive tissue contrasts with what would be expected for a neurotropic virus [55], and bolsters the above hypothesis, insofar as autoimmunity is associated with lymphopenia [57].
SARS-CoV-2 might also affect AD patients indirectly by necessitating changes to treatment indicated for the disorder. While the ACE2 activator diminazene aceturate [58] and the ARB losartan [59] have been shown to reduce AD neuropathology and improve cognitive performance, the possibility of their potentiating a more severe SARS-CoV-2 infection theoretically exists. Nonetheless, an association between angiotensin converting enzyme inhibitors (ACEI)/ARB therapy and greater COVID-19 risk was identified neither in an AD-specific [60], nor general patient context [61]. Discontinuation of ACEI/ARB therapy due to COVID-19 might be especially contraindicated in women with AD, seeing how results in mice suggest that females are likelier to experience particularly debilitating effects of pathologic ACE variants [20]. Further, activity of the cholinesterase inhibitors donepezil and galantamine frequently used as part of AD therapy may increase when used concomitantly with chloroquine/hydroxychloroquine or the antivirals lopinavir-ritonavir, both of which have been used to treat COVID-19, largely as a result of the viral therapeutics’ metabolism by cytochrome P450 (CYP) 3A4-isoform and inhibition of CYP2D6-isoform, necessitating heightened vigilance during the treatment of patients suffering from both diseases [62]. Moreover, quarantining and isolation are not conducive to cognitive exercise and so the COVID-19 pandemic may exacerbate existing neuropsychiatric facets of AD or precipitate their occurrence [28, 63, 64]. Unfortunately, some demographics may be disproportionately affected by the pandemic. A Michigan study identified that the risk for both COVID-19 and AD and related dementias is greater for Black adults [28]. Clinicians will need to integrate all of these factors if they are to provide optimal care for individuals affected by both AD and COVID-19.
The Herpesviridae family includes human herpesviruses 1 to 8 (HHV 1–8), which are common causes of many diseases ranging from the relatively innocuous cold sore (HHV-1) to debilitating Kaposi’s sarcoma (HHV-8). HHV-1, HHV-2, HHV-4, HHV-5 and HHV-6A/B warrant closer consideration due to their potential contribution to the pathophysiology of AD.
Herpes Simplex Virus (HSV) is a member of the Herpesviridae family and one of the most widespread viruses in the human population. About 80% of older adults in the USA have at one point incurred HSV infection and have serum antibodies against the virus [65, 66]. Herpes viruses are characterized by their large size, double-stranded DNA genome and ability to cause lifelong infections [67].
HSV neural infection occurs by two main routes. The first involves infecting epithelial cells of the oral and nasal mucosae, which can lead to sensory neuron ascension. Subsequent axonal transport leads to viral transmission into the central nervous system (CNS) [68, 69, 70]. The second path is that of hematogenous dissemination, where the virus crosses the BBB to enter the CNS [71, 72, 73].
HSV may result in an asymptomatic latent infection, where the virus lies dormant
within neurons until the lytic cycle is triggered by an adverse reaction to a
drug or immunodeficiency secondary to physiological aging or myriad
pathophysiological processes [74, 75]. Nonetheless, this dormant state might well
be surreptitious, with viral particles seeding pathology prior to any clinical
manifestation of disease. Multiple autopsy studies on AD patients have shown that
HSV-1 DNA is often present in regions critical to the development of AD [76, 77, 78, 79, 80, 81]. When present, HSV-1 localized predominantly to A
Apart from HSV, other members of the Herpesviridae family may
contribute to the pathogenesis of AD. HHV-3, also known as Varicella-zoster virus
(VZV), is responsible for varicella in children and herpes zoster in adults [95].
This virus is capable of causing latent infection after crossing the BBB or by
cross-axonal retrograde transport from skin vesicles [96]. In the latent state,
VZV usually inhabits the cranial nerve ganglia, dorsal root ganglia and autonomic
ganglia [97, 98, 99, 100, 101, 102, 103, 104]. A recent study found that VZV
infection is associated with an increased risk of dementia such that might be
attenuated through the administration of antiviral therapy [105]. An increased
risk for AD, irrespective of gender was also identified in a study on herpes
zoster patients above 65 years of age [33] (Table 1). VZV might be involved in AD
pathogenesis through its activity on insulin-degrading enzyme (IDE), a zinc
metalloprotease associated with A
Epstein-Barr Virus (EBV) or HHV-4 affects as much as 95% of the global population, most of whom come into contact with it in the early stages of life. While EBV infection is usually oligo-symptomatic, in some patients the virus can cause severe disease, subsequent to which the virus may remain in B-lymphocytes [110]. Recent studies have shown that this process might be associated with development of AD. Carbone et al. (2014) found EBV DNA in the blood of 45% of the AD patients participating in the study and in 6% of AD patient brain samples. Interestingly, all EBV positive brain samples originated from carriers of the pathogenic APOE E4 allele [34].
HHV-5, also known as human cytomegalovirus (CMV) also frequently results in nothing but an innocuous latent infection [111, 112]. Still, an association between CMV and AD has been made [113]. Depending on the demographic, the percentage of individuals that carry CMV blood antigens ranges from 20% up to 100% [114, 115, 116]. Some reports suggest that infection with CMV may be associated with cognitive impairment. According to Aiello et al. [114], a significant proportion of patients with increased levels of CMV blood markers experienced a substantial drop in cognitive performance after a 4-year period. Further, significant elevation of CMV markers was reported in a group of individuals over the span of 5 years, during which period they developed clinical AD [34] (Table 1). Importantly, plasma CMV IgG levels were found to correlate with increased density of neurofibrillary tangles (NFTs) [117].
Human betaherpesvirus 6A/B (HHV-6A/B) can enter the CNS via the olfactory tract
leading to HSV-1 like latent infection [118]. Nonetheless, damage to glia and
neurons post HHV-6 infection has been reported [119, 120, 121, 122, 123, 124].
Multiple reports point to a large association between HHV-6 and AD. A study by
Readhead et al. [125] on more than 1000 brain samples showed high levels
of HHV-6 in the tissue of AD patients. Eimer et al. [126] demonstrated
that increased A
Hepatitis C virus (HCV) is a small, single-stranded, enveloped virus that can
cause chronic hepatitis and puts individuals at increased risk of developing
hepatocellular carcinoma. Recent studies have shown that 2.8% of the global
population may be infected with HCV which corresponds to more than 185 million
cases worldwide [130]. An association between HCV infection and CNS
manifestations was first discovered over 15 years ago, since which time our
understanding of the neurotropic nature of the virus has grown considerably
[131]. While HCV has been identified as a risk factor for AD, how the virus is
involved in neurodegeneration remains to be elucidated. Still, two
non-mutually-exclusive mechanisms have been suggested. HCV may cross the BBB and
directly exert toxic effects on neuronal tissue or initiate CNS or systemic
inflammation conducive to neurodegeneration [132]. Another possible link between
HCV infection and AD is based on virally-induced overexpression of cholesterol
25-hydroxylase gene (CH25H) and consequent overproduction of
25-hydroxycholesterol (25OHC) [133, 134]. Cholesterol containing lipid rafts are
thought to potentiate viral entry into cells but likewise serve as hubs for
pathologic cleavage of APP [135]. Interestingly, the type-I interferons (IFN)
generated in response to HCV infection that drive overexpression of
CH25H may prime 25OHC to block virus-cell membrane fusion [134, 136, 137]. In mice treated with the toll-like receptor 4 (TLR4) agonist,
lipopolysaccharide (LPS), 25OHC synthesis was greatly augmented and accompanied
by increased CNS production of the pro-inflammatory cytokine IL-1
The Influenza A virus is characterized by a single-stranded segmented genome and
is a chief causative agent of the seasonal flu. The virus is known to undergo
both antigenic drift and antigenic shift, the latter of which, particularly, has
given rise to epidemics including the avian flu and the swine flu, caused by the
serotypes of hemagglutinin-5-neuraminidase-1 (H5N1) and
hemagglutinin-1-neuraminidase-1 (H1N1), respectively. Serotypes are named
according to variants of the viral proteins hemagglutinin (H) and neuraminidase
(N), which, broadly speaking, allow the virus to gain entry into host cells and
facilitate lysis after intracellular replication is complete, respectively.
Interestingly, H5N1 has been implicated in the phosphorylation and aggregation of
alfa-synuclein (ASN), whose role in Parkinson’s disease (PD) neurodegeneration
has been well established [37]. While the said pathology plays a more obvious
role in the pathogenesis of Lewy body dementia and PD, the structural similarity
between A
A
Another influenza serotype that might also be related to a pathological neural changes is CA/09 H1N1. This virus does not actively cross the BBB and is thought to be non-neurotropic [38]. Nonetheless, in one study it was shown to lead to microglial overactivation that remained pronounced for three weeks post infection and was sustained to a lesser degree for as long as 90 days [38]. The infection was accompanied by down-regulation of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), genes which encode neurotropic factors essential for maintaining neural plasticity. Furthermore, BDNF and GDNF are responsible for regulating microglial activation, and their decreased expression may lead to CNS inflammation, which coupled to reduced brain plasticity, increases the risk for AD dementia [38].
The neurodegenerative effects of viral infection have been summarized in Fig. 1.
The pathomechanism of virus-associated neurodegeneration. Herpes simplex virus 1 (HSV-1) resides in neurons and may induce aggregation of
A
The first hypothesis linking prokaryotic microorganisms and AD was forwarded by Alzheimer and other scientists in the early 20th century [148]. Recent research trends point to a recrudescence in conjecturing about the role of prokaryotes in neurodegeneration. In addition to transmissible infections, natural florae of the oral cavity, lungs, gastrointestinal tract, and urinary tract may become dysregulated due to pharmaceuticals or physiological changes and cause disease. Importantly, inflammation secondary to bacterial infection must be considered in addition to the potential direct pathologic effects of microorganisms on the CNS.
Among the bacteria capable of inducing excessive inflammation in the CNS are
spirochetes [149, 150]. Spirochetes are gram-negative, helical bacteria, with
neurotropism for the trigeminal ganglion and nerve [151, 152]. They are able to
penetrate the host by utilizing three different mechanisms: hematogenous
dissemination, ascension along nerve fibers of the tractus olfactorius
and adjacent fila olfactoria, and via the lymphatics. Recently,
spirochetal invasion of the olfactory tracts and bulbs of patients with early
evidence of AD neurodegeneration was demonstrated [153]. Once in the CNS
spirochetes may lead to latent infection [154, 155]. The presence of spirochetes
has been reported in the CSF, blood, and brain of AD patients, with neural
invasion being 8-fold more frequent among those with AD as compared to controls
[152, 155, 156]. Seeing how spirochetes may require amyloid like
proteins in order to maintain their lifecycle in the CNS, bacterial amyloids
could promote A
The spirochetes that are most widely researched in the context of AD are
Borrelia burgdorferi and Treponema pallidum. B. burgdorferi is
the causative agent of Lyme disease (borreliosis), in the late phase of which
bacterial infection may lead to cortical atrophy and microgliosis, which are
considered to be precursors of dementia [155, 158]. Currently, the number of
borreliosis cases is steadily increasing in European countries and thus, a
growing number of researchers are probing the possible association between
spirochetal invasion of the brain and development of AD [158]. The presence of
B. burgorferi in the cerebral cortex of the brains of AD patients was
shown for the first time in studies by MacDonald and Miklossy and co-authors [39, 159]. The chronic inflammation induced by B. burgorferi may result in
abnormal phosphorylation of the protein tau, leading to microtubule dysfunction
and NFT formation. In a group of patients suffering from both AD and
neuroborreliosis, B. burgorferi antigens were detected in numerous
structures including NFTs, A
Chlamydia pneumoniae is a Gram-negative intracellular pathogen
antibodies against which are detectable in as many as 80% of individuals between
60 to 70 years of age [165]. Presumably, chlamydia are able to penetrate to the
CNS via the olfactory route, similarly to other, previously discussed
microorganisms [166]. The presence of C. pneumonia in the CSF and brain
of AD patients has been highlighted by many authors [167, 168, 169, 170, 171, 172]. Balin et al. [168] identified C. pneumonia in 17 of 19
post-mortem frozen brain fragments from AD patients, as compared to a single
positive PCR-test result in control brain samples. Similar results were obtained
by Gérard et al. [170] who detected C. pneumonia in 20 of
25 AD postmortem brain samples and in only 3 of 27 from the control group.
Importantly, infected cells co-localized nearby senile A
Recent studies have pointed out that the oral cavity may be one of the most important reservoirs of bacteria capable of infecting the brain and promoting the onset of dementia. Periodontal disease may induce a systemic inflammatory response thereby effecting changes at distant sites. Amid the pathogens causing periodontitis, the potential involvement of Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, Fusobacterium nucleatum, Aggregatibacter actinomycetemcmitans, Eikenella corrodens and Treponema denticola in the pathogenesis of AD has been considered, but detailed commentary on each is beyond the scope of this review [175, 176].
Periodontitis leads to the destruction of tissues surrounding the teeth and is a
significant problem predominantly affecting the elderly [177, 178]. In 2019, the
NHANES III study showed that periodontitis was significantly associated with
cognitive impairment [43]. The symptoms of periodontitis, including gingival
bleeding, loss of periodontal attachment, and finally loss of teeth are caused by
bacterial LPS which provokes the immune response to generate tumor necrosis
factor
Propionibacterium acnes is another periodontal pathogen possibly associated with the risk of developing AD. These bacteria may enter the CNS and infect the brain via hematogenous spread [186]. In young individuals, the bacteria usually act as epidermal commensals, but are a common cause of acne vulgaris. Still, P. acnes has been identified in the frontal cortex of patients with AD [44]. While a connection between P. acnes infection and AD has not yet been firmly established, there are reports indicating that in some cases effective treatment against P. acnes, such as cephalosporine combined with estrogen and enalapril may lead to memory improvement and stabilization of clinical symptoms, as shown in two AD case reports [44, 151].
Helicobacter pylori is a curved, Gram-negative bacterium that may lead
to stomach ulcers and gastric cancers and is estimated to be present in more than
50% of the population worldwide. Apart from its effects on the gastrointestinal
system, many studies have implicated H. pylori in other diseases, such
as respiratory or neurodegenerative disorders [151, 187]. Kontouras et
al. [188] showed that among 27 AD patients, 100% presented with high levels of
anti H. pylori IgG antibodies in the serum and CSF. A 20-year
longitudinal study performed on 603 patients above 65 years of age showed that
the presence of IgG antibodies against H. pylori was associated with a
1.46 fold increased risk of developing dementia, as compared with the control
group [45] (Table 1). Further, in vitro studies performed using mouse
neuroblastoma N2a cells transfected with the human APP gene demonstrated
that cells infected with H. pylori produced increased presenilin 2 (PS2)
and A
The pathomechanism of bacteria-associated neurodegeneration. The infection of the central nervous system by Borrelia burgdorferi
activates microglia to produce proinflammatory cytokines—e.g.,
interleukin-1
The eukaryotic protozoa, among which numerous human parasites may be identified, might also influence the start and course of neurodegeneration. Only Toxoplasma gondii, whose effects on cognitive functioning have been relatively well characterized will be considered here. T. gondii is an intracellular pathogen with multiple intermediate hosts, but mainly parasitizes warm-blooded animals. T. gondii infection affects approximately 30% of the global population with its prevalence varying depending on sanitary conditions, educational and cultural background, and profession [193]. T. gondii spreads via oocysts, thick-walled spores resistant to environmental conditions. In humans, consumption of oocyst contaminated water or food and placental transmission are the main routes whereby infestation with the parasite occurs [194]. In immunocompetent patients, the initial phase of infection is oligosymptomatic. Nevertheless, at this stage T. gondii spreads through the organism as a tachyzoite, a rapidly-proliferating form recognized by the host immune system [195, 196]. Monocytes and dendritic cells recruited during this initial immune response undergo activating changes including actin cytoskeleton remodeling, signaling downstream of the gamma-aminobutyric acid (GABA) receptor, and upregulation of the chemokine receptor CCR7 [197, 198, 199]. During the persistent phase, the protozoan transforms into a slow-growing bradyzoite and encysts. This form strives to avoid the immune response and resides in various human tissues, primarily in the CNS and muscles leading to chronic and latent infection [200]. The exact mechanism through which the parasite crosses the BBB is still unknown, however, there are several hypotheses for how T. gondii might invade the CNS. In a trojan horse-like mechanism, infected monocytes display increased mobility and transfer T. gondii across the BBB into the CNS [201, 202, 203]. In transendothelial migration, infected cells express cluster of differentiation molecule 11B (CD11b)/intercellular adhesion molecule 1 (ICAM1) integrins, which facilitates parasite adhesion and migration across endothelial cells [199, 203, 204]. Finally, in paracellular migration protozoa gain access into the CNS via actin-myosin motors, exhibiting a movement called “gliding motility”. This allows the parasites to elide host immune barriers and penetrate across tight junctions as well as polarized cell monolayers. Increased expression of T. gondii adhesive microneme protein 2 (MIC2) and excessive interaction with the ICAM-1 is thought to allow passage across highly selective biological barriers including the BBB [205, 206].
How long-term infection influences neurological functions is still largely
unknown [207, 208]. Recent studies have shown that persistent exposure to
T. gondii might increase the risk of developing neurodegenerative
disorders such as AD and PD, as well as schizophrenia, migraine and bipolar
disorder type I [209, 210, 211, 212]. Importantly, a significant association
between the presence of antibodies against T. gondii in elder
patients and impaired cognitive abilities has been identified [32]. Studies based
on animal models have shown that chronic toxoplasmosis may also cause behavioral
alterations such as neophobia, affect learning, and disrupt memory [213]. Mice
with toxoplasmosis were shown to have reduced nerve fiber density and loss of
synapses in infected brain zones, and especially in somatosensory areas [214].
In vitro studies have reported that T. gondii can infect and
form cysts in astrocytes and neurons, but only the former are capable of
eliminating the intracellular form of the protozoan [215, 216, 217, 218].
Additionally, several simulations have revealed that toxoplasmosis might cause
tau hyperphosphorylation and A
One of the mechanisms responsible for the appearance of AD-like symptoms in
toxoplasmosis may be altered glutamine, dopamine or GABA neurotransmission [219, 221]. Specifically, T. gondii infection might impact the glutamatergic
N-methyl-D-aspartate (NMDA) receptor (NMDAR), which mediates
neurotransmission at excitatory synapses and participates in synaptic plasticity
[222]. Studies performed in wild type mice have shown that toxoplasmosis may
induce increased expression of NMDARs in the cortex and hippocampus, as well as
production of hyperphosphorylated tau and A
The next neurotransmitter presumably related to AD-like symptoms in
toxoplasmosis is GABA, the main inhibitory neurotransmitter in the CNS [224]. The
cognitive deterioration that occurs in some cases of the disease may be related
to T. gondii-induced disruption of GABA turnover [225]. It is known that
changes to the GABAergic system including reduced expression of the GABA receptor
Dopamine is responsible for controlling a wide range of neurological functions including motor skills and pathways governing motivation and as such, a dysfunctional dopaminergic system might trigger some of the neuropsychiatric manifestations of AD [230]. Correlations exist between AD and a dysregulated dopaminergic system particularly in the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the locus coeruleus (LC). Murine models of AD have evidenced significant changes in memory processes and cognitive abilities caused by dopaminergic neuron impairment in the VTA [231]. T. gondii exerts an effect on the dopaminergic system by leading to decreased expression of the dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2). In addition, two genes in the T. gondii genome, aromatic amino acid hydroxylase 1 and 2 (AAH1 and AAH2) encode enzymes which may be involved in production of l-3,4- dihydroxyphenylalanine (L-DOPA) [232]. These mechanisms may induce increased dopamine concentration in synapses. Indeed, underexpression of the genes dopamine receptor D1, -D2 and D4 (DRD1, DRD2 and DRD4, respectively) and G protein-Coupled Receptor Kinase 6 (GRK6) causing decreased dopamine receptor availability led to elevated dopamine levels in mice with toxoplasmosis [221]. Abnormal dopamine levels can disrupt motor and executive functions and lead to the development of symptoms characteristic of neurodegenerative disease. Moreover, it has been demonstrated that hyperactivity of dopaminergic neurotransmission pathways impacts prefrontal cortex functions and may lead to cognitive impairment [233].
While T. gondii infection may be associated with cognitive decline
through its ability to dysregulate neurotransmission, it has not been found to
promote aggregation of pathological proteins. Two independent teams of
researchers working on AD-mice models infected with Toxoplasma strain
Type II evidenced that chronic toxoplasmosis may actually reduce A
The possible effects of Toxoplasma gondii infection on
brain cells. AMPAr, AMPA receptor; DA, dopamine; DAr, DA receptor; GABA, gamma-butyric acid;
GABAr, GABA receptor; NMDAr, NMDA receptor; A
In summary, T. gondii infection may constitute a potential risk factor for AD (Table 1), however, the mechanisms whereby it might seed neurodegenerative changes in the brain are still unclear and require further research.
AD is the most common cause of progressive, irreversible dementia in older adults and constitutes a vital socioeconomic issue in developed countries with aging populations. While it is known that AD is a multifactorial disease, affected by both genetic and environmental factors, its pathogenesis is not fully understood. Moreover, existing pharmacotherapy for AD is limited and provides only moderate relief for patients in the early stages of the disease. Despite years of research focused on molecular mechanisms of neurodegeneration, there is still no treatment that addresses the cause of AD.
Recently, increasing attention has been placed on the microorganismal hypothesis
of AD development. Studies have demonstrated that microorganisms frequently
co-localize with pathological changes in the CNS, suggesting that viral,
bacterial and parasitic infections may contribute to neurodegeneration. Multiple
reports have shown that infectious agents may facilitate the A
25OHC, 25-hydroxycholesterol; AAH1/2, aromatic amino acid hydroxylase
1/2 coding genes; ACE, angiotensin-converting enzyme 1 coding gene;
ACE1/2, angiotensin-converting enzyme 1/2; ACEI, angiotensin converting enzyme
inhibitors; AD, Alzheimer’s disease; ADAM-9, alpha-secretase a disintegrin and
metalloproteinase-9; ADDLs, A
TP—preparing the part concerning putative contribution of SARS-CoV-2 in a pathogenesis of Alzheimer’s disease; whole manuscript language correction; MH—preparing the part concerning possible role of viral agents (except SARS-CoV-2) in the pathogenesis of Alzheimer’s disease; NB—preparing the part concerning putative contribution of bacterial agents in the pathogenesis of Alzheimer’s disease; PS—preparing the part concerning possible association of Toxoplasma gondii in the pathogenesis of Alzheimer’s disease; JD—formulating of the article frames, substantive consulting, correction of the manuscript; WK—substantive consulting, correction of the manuscript; MP—preparing the abstract, introduction and conclusion sections, preparing all the figures, work management, substantive correction and formatting of the article.
Not applicable.
This work was co-supported by the Polish National Centre for Research and Development (NCBiR) (co-funded by the European Union), grant no. POWR.03.01.00-00-T006/18-00, and by the Poznan University of Medical Sciences, Student’s Scientific Association (STN), grant no. 502-05-11111440-05851.
This research received no external funding.
The authors declare no conflict of interest. JD is serving as Guest Editor of this special issue and one of the Editorial Board members of this journal. We declare that JD had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to RF.