AD is a neuropsychiatric ailment; found most frequently in people above 65 years, has affected millions of people worldwide. The World Health Organization (WHO) [76] has described the disease as a cognitive impairment that gradually affects behavior, mood, memory, and learning [77, 78]. Neurofibrillary tangles (NFTs) are derived from the paired helical filaments (PHFs), which are the hyperphosphorylated forms of the axonal protein “tau”. Proteases cleave the senile plaques (SPs), which are derivatives of the amyloid precursor protein (A$\beta$PP) to form A$\beta$ protein. The intracellular (NFTs) and $\beta$-amyloid (A$\beta$) peptide oligomer deposition are evident in AD. The aggregation and spreading of these oligomeric structures to the extracellular environment and all over the brain can cause synaptic toxicity and neuronal death [79, 80]. It is also evident that the NFTs and A$\beta$ peptide accumulation increases with age. The aggregated A$\beta$ and tau protein may leak from the brain to the external environment, such as cerebrospinal fluid (CSF) [81]. However, extensive research on neurodegeneration has explained several factors other than aging, which can trigger the accumulation of NFTs and A$\beta$. One of such neuromodulation, induced by inflammation, also results in the development and progression of AD.

In mammals, the microglia present in the brain is the key factor that links neuroinflammation and neurodegeneration. Microglia can be activated by several factors such as infectious agents (bacteria, viruses, fungi), advanced glycation end products (AGE) receptors, A$\beta$ and tau protein, and neurotoxins that include antibodies, cytokines, iron-rich-complement factors, and chemokines (such as toll-like receptors TLRs) [82]. These are considered as danger signals that may pose a threat to CNS homeostasis. In general, the activated microglia serves as the first line of defense that releases inflammatory molecules to combat infection and toxins, regulates astrocytes’ activation, and engulfs the tau and A$\beta$ by phagocytosis [83]. It plays a major neuroprotective role in the inflammatory processes, which involves activation of astrocytes and release of signaling molecules, mainly neurotoxic factors like (superoxide radicals (O${}_2$${}^{-}$), nitric oxide (NO) and ROS), growth factors, major histocompatibility complex II (MHC-II) molecular pattern recognition receptors (PPRs), tumor necrosis factor-alpha (TNF-$\alpha$) and cytokines (interleukin (IL) 1 beta (IL-1$\beta$), IL-6, IL-12 and interferon (IFN) gamma (IFN-$\gamma$)) [84, 85]. These signaling then possibly change the blood-brain barrier (BBB) permeability and generate various lesions in the brain and CNS [86]. The activated microglia and the neuro-immunomodulatory signaling can switch the role from neuroprotective to neurotoxic and pose a risk of development and progression of AD [87].

The oligomer A$\beta$ formed in mammals is possibly phagocytosed by the activated microglia, which promotes the NLRP3 inflammasome activation, triggering microglia to release the cytokine interleukin-1$\beta$ (IL-1$\beta$). The phagocytosed A$\beta$ then activates the death of the lysosomes, followed by production of the cathepsin B from it. The released cathepsin B now activates caspase-1, which further triggers the production of IL-1$\beta$ from the pro-IL-1$\beta$. Subsequently, more microglia was activated by the IL-1$\beta$ maturation [88]. Reports have proposed that the lower the caspase-1 and IL-1 IL-1$\beta$ activation in the brain, the higher the A$\beta$ phagocytosis, which subsequently reduces the probability of spatial memory loss and AD related deficiencies [89]. However, a study on the murine model (APP/PS1) of AD deficient in NLRP3 inflammasome has reported a decline in the A$\beta$ deposition suggesting the importance of NLRP3 in AD onset and progression [90].

It has been observed that the patients with AD have an upregulated IL-1-NF-$\kappa$$\beta$ immune signaling, but the mechanism of disease is still poorly understood [91]. Research on the mammalian model suggested that glial cell receptors can identify different forms of A$\beta$. They further activate different pathways; for instance, the advanced glycation end products (AGES) or CD36 receptors could recognize fibrillar A$\beta$ to sensitize Toll-like receptors (TLRs). In contrast, the CD36 receptor recognizes soluble (nonfibrillar) A$\beta$ and triggers its phagocytosis by microglia [92]. Similarly, nonfibrillar A$\beta$ matured from soluble A$\beta$ leads to the formation of NOD-like receptor protein 3 (NLRP3) inflammasome, promoting IL-1 IL-1$\beta$ [73], which later may facilitate the onset of AD.

On the other hand, in D. melanogaster, the A$\beta$ deposits are recognized by the glial engulfment receptor called Draper, which activates the Draper/STAT92E/JNK signaling pathway and downstream protein degradation lysosomal-related pathways to phagocytose A$\beta$ deposits [93]. The AD flies deficient with the IMD pathway are marked with the Draper activated glial cells accumulation around the $\beta$-amyloid plaques [94]. Earlier reports on D. melanogaster suggested that loss of function of Draper intensifies the ç42-induced toxicity, which then leads to impaired locomotion and a short life span. At the same time, overexpression of Draper reduces A$\beta$42-induced toxicity and moderately improves fly longevity and defective locomotion [93]. Mammalian TNF-R pathway, homolog Imd pathway play a neuroprotective role in D. melanogaster by activating the NF-$\kappa$$\beta$ signaling, which then induces the microglial-mediated engulfment of extracellular A$\beta$ pools [94]. A study revealed that mutation in the transmembrane receptor ‘D. melanogaster Toll (Tl) gene’, a homolog of the mammalian IL-1 receptor, reduces the A$\beta$42 neuropathological activity in D. melanogaster, but the gain of function of the toll receptor enhances the A$\beta$42 neurotoxicity activity. Thus, when the Tl- NF-$\kappa$$\beta$ pathway is suppressed genetically, it causes a reduction in the neuropathological activity of A$\beta$42 [91].

Previous reports suggest that deposits of A$\beta$ in mammal activates and recruits the microglia which in turn phagocytoses them and releases pro-inflammatory cytokines but mechanism after the phagocytosis of A$\beta$ still not known [95], so D. melanogaster can be used to decode inflammation-mediated AD pathogenesis.

PD is the second most common neurodegenerative disease after AD, accounting for approximately 2% of the population. Patients suffering from PD have difficulty in movement (bradykinesia), dementia such as LB dementia (DLB), multiple-system atrophy (MSA), and neuropsychiatric dysfunction, and rest tremor, instability in body posture, rigid movements, hallucinations, hypotension, and constipation [96, 97, 98]. PD is a multifactorial disease caused by various factors such as the deposition of $\alpha$-synuclein ($\alpha$-syn) oligomers, dysfunctional oligomers, neuroinflammation, oxidative stress, and aging. PD patients have mainly marked with degeneration in neurons of substantia nigra pars compacta that contains neuromelanin. The major hallmark of PD is the degradation of the dopamine and aggregation of Lewy bodies (LBs-the cytoplasmic protein) composed of $\alpha$-syn filaments [99]. Thus, dopamine amendments consequently promote dysregulation in the basal ganglia, which then triggers dysfunctional motor activities.

PD can occur from multiple damage signals such as endogenous proteins, pathogens, toxins or toxic agents, dying neuron products, and aging. It has been reported that the vascular channels connecting the brain to the skull employing meninges might direct the microbes or the non-cerebral immune cells to enter into the brain region [100] to evoke the damage signals. The inflammatory cascade activated by damage signals causes synaptic impairment, leading to the penetration of more inflammatory molecules to the mid-brain and triggers more microglia production, increasing ROS and eicosanoid generation dopaminergic neurons death that ultimately results in PD associated neurovascular dysfunctions [101]. PD patients are found with an enhanced inflammatory response such as activation of the peripheral lymphocytes and releasing the pro-inflammatory serum cytokines IL-2, IL-6, IFN-$\gamma$, and TNF-$\alpha$, leading to the development of neurotoxicity [102]. Martin et al.’s [103] study on mice PD model suggested that induction of the inflammatory processes causes elevation of the MHC II in astrocytes and microglia residing in ventral midbrain. The bone marrow-derived leukocytes are also capable of triggering neuroinflammation in the brain tissue and leading to the onset or progression of PD and other brain pathologies [104].

PD pathogenesis caused by infections often mediates neuroimmunomodulation. Neuroimmunomodulation includes an increase in aggregation of substrates such as adenosine triphosphate, $\alpha$-syn, metalloproteinase-3 (MMP-3), and neuromelanin from degenerated neurons [103]. Watson et al. [105] demonstrated the activation of microglia and inflammation in the $\alpha$-Syn overexpressed mouse. The $\alpha$-syn also causes MyD88 activity-dependent microglial activation by activating TLR 1/2 [106]. The degenerated neurons are the outcomes of multiple factors such as $\alpha$-syn-mediated phagocytosis, activated TLR4 microglia, presence of proinflammatory cytokines (IL-6$\beta$, TNF-$\alpha$, TGF-$\beta$, and IFN-$\gamma$), presence of ROS, and incidence of $\alpha$-syn activated astrocytes localized in nigrostriatal regions and CSF of PD patients [107, 108, 109]. The activated microglia can engulf the $\alpha$-syn and initiate its degradation by the lysosome. Still, failure in the degradation of $\alpha$-syn aggregates triggers cathepsin B from lysosomal chamber and also activates NLRP3 inflammasome formation, which ultimately causes pathogenesis of PD [110]. The elevated level of key inflammatory molecules contributes to inflammation-related neurotoxicity in PD [111, 112].

In PD-affected people, the role of lysosomal dysfunction is well studied. The lysosomal autophagy system (LAS) and the ubiquitin-proteasome system maintain the proper amount of intracellular $\alpha$-syn [95]. Lysosome plays a significant role in fibrils ($\alpha$-syn) trading through tunneling nanotubes (TNTs) present in the middle of the neuron, stimulating misfolding, and deposition of soluble protein [113]. But a lysosomal dysfunction can initiate the escaping of the $\alpha$-syn to neighbor cells which may cause brain invasion and disease progression [114]. These $\alpha$-syn are cleaved by caspase-1 and aggregate as Lewy bodies in the dopaminergic neurons of mammals and activate the microglial cells. These further stimulate excessive production of tumor necrosis factor-a (TNF-a) and IL-1 IL-1$\beta$ in the substantia nigra pars compacta regions resulting in neuroinflammation mediated neuron death [106].

D. melanogaster also exhibits complex behaviors such as aggression, grooming, courtship, learning, conditioning to fear, and locomotory activities such as climbing, flying, and walking [115] which gets, impaired by PD pathogenesis. PD mutant flies are observed with loss of DA neurons and defective motor activity. The paraquat-induced Drosophila PD model is witnessed with activated signaling factor of Toll, IMD and c-Jun N-terminal kinase (JNK) [116]. Maitra et al. have also demonstrated the crucial role of Relish to rescue mobility defects and neuronal loss in flies. Infection-mediated Relish activation via IMD signaling leads to the induction of NF-$\kappa$$\beta$ signaling in D. melanogaster that finally culminates in increased AMP production [117, 118]. This rise in the Relish-dependent AMPs level can lead to neurodegeneration.

Mammalian mitochondria featuring multiple functions can be a central driver of diseases owing to their dysfunction caused by aging, disease (autoimmune diseases, cancer, metabolic disorders, and neurodegeneration), exposure to toxicants of the environment, and pathogenic infection. Dysfunction of mitochondria results in impaired oxidative phosphorylation (OXPHOS) and metabolism, accumulation of unfolded proteins, loss of membrane potential, and enhanced ROS generation. It regulates a wide range of cellular processes and houses the molecules involved in the antiviral and inflammasome signaling and endogenous damage-associated molecular patterns (DAMPs). These mitochondrial DAMPs engage the innate sensors/PRRs to activate pro-inflammatory and type I IFN responses [119]. Numerous studies have revealed the association of mitochondrial dysfunction with the pathogenesis of PD in humans [120]. Mammalian mitochondria also possess many sophisticated systems that participate in the proper functioning of the protein and maintain the cell’s structural integrity. These systems, comprising AAA proteases, the ubiquitin-proteasome system, mitochondrial-derived vesicles (MDVs) and mitophagy, and fission/fusion regulatory system, taken together is referred to as mitochondrial quality control (MQC) [121]. In the past few years, the role of PTEN-induced putative kinase 1 (PINK1) and PRKN in the activation of the MQC machinery in response to mitochondrial dysfunction has been extensively studied [122, 123]. Under unpleasant conditions (mitochondrial damage, mutagenic stress, and proteotoxicity), the intermembrane transport of PINK1’s N-terminus from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) is impaired, resulting in PINK1 accumulation on the OMM. The accumulated PINK1 triggers autophosphorylation, which facilitates kinase activation and promotes binding to the Parkin and ubiquitin [124, 125]. Now activated Parkin facilitates the formation of the ubiquitin chains and attracts more Parkin to the mitochondria, thereby amplifying the damage detecting signals received by PINK1 [126]. The recruited Parkin leads to ubiquitination of many cytosolic targets such as Parkin Interacting Substrate (PARIS, ZNF746) and AIMP2, whose accumulation may cause neurotoxicity and cell death of nigral DA neurons [127, 128].

Moreover, mutations in these genes are linked to the autosomal recessive forms of PD in mammals [129, 130]. Autosomal recessive juvenile parkinsonism (ARJP) results from the dysfunctional LAS and E3 ubiquitin-ligase system produced from a mutation in the parkin gene [131]. However, the mechanism of the development of ARJP pathogenesis is still not clearly understood. Loss of function PINK1/Parkin MQC machinery may alter the correlation between CNS and peripheral immune system and evoke an adaptive immune response against mitochondrial proteins. Thus, compromised PINK1/Parkin MQC engages the peripheral immune system in an attack against CNS. Loss of Parkin impairs the generation of mitochondrial-derived vesicles (MDVs) required for bactericidal activity, resulting in the defect in clearance of infection causing chronic infection and enhanced cytokine production [132].

In D. melanogaster, PINK1/Parkin shows similarities in pathways to maintain mitochondrial fidelity with mammals but differs in its localization [133]. Greene et al. [134] studies demonstrated dysfunctional mitochondria and damaged flight muscle phenotypes in the D. melanogaster model mutant for the parkin gene. Moreover, these parkin mutant flies have also shown higher oxidative stress levels and altered levels of parkin and oxidative stress genes. Lastly, when they induced the innate immunity genes in the parkin mutant flies, the cell cycle and the endoplasmic reticulum stress regulatory pathways are altered, resulting in the inflammation-mediated ARJP pathogenesis. The PINK1/Parkin KO mutant flies are observed with a decline in male sterility and life span, impaired locomotor activity, mitochondrial dysfunction in muscle and brain, and defective DA neuron morphology [135, 136]. Loss of function of Parkin in Drosophila leads to the reduced motor activity, shrinkage of DA neurons, and decline in the level of tyrosine hydroxylase [137]. Flies with PINK1 mutation have similar phenotypic defects (impaired locomotion, defective DA neurons, and reduced life span) as that of parkin mutant flies [136]. Additionally, loss of function of PINK1 causes defective thorax phenotype in young flies (3 days old) and leads to age-dependent DA neurons deficiency in PPL1 cluster in 30 days old flies [138].

ALS is a fatal neurodegenerative disorder evident in approximately 2 people per 100,000 and usually causes the death of the patients within 3–5 years [139, 140, 141]. Men are slightly more prone to the disease than women. ALS patients exhibit weakness of limbs and are thus diagnosed with upper and lower body motor neurons defect [142]. Along with motor disorders, ALS patients are also diagnosed with dementia, sensory abnormalities, and autonomic dysfunction [143, 144, 145]. Many factors play a role in the pathogenesis of ALS, such as environmental hazards, immunological disorders, and inflammation. ALS is identified with a genetic mutation in the superoxide dismutase 1 (SOD1) [146]. The mutation in SOD1 covers only 20% of the total identified ALS cases suggesting probability of mutations in other genes. Modification of the gene encoding transactive response DNA-binding protein-43 (TDP-43), i.e., TARDBP and mutation in the gene encoding sarcoma fusion/translocation in liposarcoma, is also responsible for ALS [147].

Meissner et al. [148] reported that the endocytosed mutated SOD1, when relocated to the cytosol, acts as a danger signal, leading to activation of the caspase1 in the mammalian SOD1 mutant microglial cells. Then the activated caspase-1 activates IL-1 IL-1$\beta$, which in turn causes neuroinflammation-induced motor neuron disease progression, a hallmark of ALS. Another common feature of ALS is the massive accumulation of the TDP-43 in certain brain regions affecting the motor neurons and activating the relocation of the NF-$\kappa$$\beta$ from the cytoplasm of microglial cells to its nucleus [149]. Several studies have also reported the involvement of the CD14 in the IL-1 IL-1$\beta$ production from microglial cells and on the TDP-43 mediated NLRP3 inflammasome activated phagocyte surface [150].

D. melanogaster acts as a good model to investigate the TDP-43 neurotoxicity and related disease. Zhan et al. [151] has reported the vital contribution of the leucine kinase Wallenda (Wnd) and p38 and JNK (downstream components) in the TDP-43 mediated neurotoxicity, and thus any genetic variation in the Wnd expression or its antagonist may improve the fly life-span by canceling the negative effect of TDP-43. Furthermore, overexpression p38b or loss-of-function of Basket (Bsk), a homolog of JNK, has exhibited a shorter fly life span and increased TDP-43-associated lethality [151]. In a nutshell, the cytoprotective role and cytotoxic effect of the JNK signaling and p38 signaling, respectively, have been well-studied in the D. melanogaster model. However, the conversation of the same in humans still needs to be explored.

The Polyglutamine (poly Q) diseases are of 9 types, namely; Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy, spinobulbar muscular atrophy, and spinocerebellar ataxias types 1, 2, 3, 6, 7, and 17; featuring CAG-trinucleotide repeats expansion along with the open reading frame (ORF) in the corresponding genes [152]. These groups of genetic diseases are marked with the deposition of the multiple inclusion bodies comprising polyglutamine-rich proteins (insoluble) that can bring about neurodegeneration in different brain regions [153]. HD is a well-studied autosomal polyQ disease featuring CAG repeats in the Huntingtin (HTT) gene. Genetic abnormality caused due to mutated HTT subsequently causes progressive atrophy of the cortex and striatum [89].

The samples collected from plasma and affected regions of HD patient’s brains exhibit increased TNF levels hinting at the role of inflammation (microglia cells recruitment and proinflammatory cells activation) in producing an unpleasant physiological state in the brain and disease progression [154]. Elevated levels of IL-1 IL-1$\beta$, hyper activated glia cells, higher levels of complement pathway components (C3 and C9), overexpression of cytokines in the brain areas of HD patients are evidence of inflammatory responses [155].

To elucidate onset/progression of polyQ diseases mainly HD and spinocerebellar ataxia type 3 (SCA3), D. melanogaster is recently used as a model organism. Transgenic flies’ mutant for transgenes encoding for ATXN3 and HTT are generated to investigate cellular and molecular mechanisms of the disease [152]. Jackson et al. have reported adult fly retinal degeneration in the SCA3 and HTT mutant flies [152, 156, 157]. Thus, D. melanogaster retina can be used as a model to decipher the link between the polyQ mediated neurodegeneration in the retina and pathogenesis SCA3 and HD mutants [152]. Evolutionary conserved innate immune (Toll and IMD) pathways in D. melanogaster play a pathological role in developing polyQ-mediated neurodegeneration. These immune signalling in D. melanogaster are involved in the inhibition of the Yorkie (Yki) a transcriptional coactivator of the Hippo pathway, by accumulated polyQ, leading to enhanced AMPs expression and the onset of neurodegeneration. Altogether, this validates an interrelation between immune pathway and neurodegeneration. Dubey and Tapadia have reported that Yki in humans can negatively regulate the innate immune pathways and reduce the polyQ neurotoxicity either by overexpressing Yki or by triggering cyclin E/bantam mediated cell proliferation in the affected cells [158].

Shieh and colleagues characterized 160 genes responsible for differential expression signatures, including genes associated with innate immune responses in the fly model having CAG repeat-associated neurodegeneration. The authors have also explored a correlation between inflammation and polyQ mediated neurodegeneration as they observed overexpression of Hsp70 and AMPs, especially metchnikowin in CAG repeat fly model [159]. Involvement of Hsp70 is also found in the human polyQ and other human neurodegenerative disease suppression [160]. These works suggest that the mechanism of inflammation-mediated neuro-pathogenesis is highly conserved between flies and humans. Shieh et al. [159] also identified genes, namely; DpId, Orb2, and Tpr2 in flies which can modify the Ataxin-3 polyQ protein toxicity and CAG-repeat RNA-based pathogenicity. Altogether, these reports suggest that the genetic modifiers identified in flies can be targeted in the mammalian model to establish a relationship between RNA/protein toxicity mediated polyQ pathogenicity [157].

Mutation in the gene Ataxia telangiectasia mutated (ATM) (that encodes for a protein kinase responsible for maintaining genomic integrity) results in a recessive autosomal neurodegenerative disease called Ataxia telangiectasia (A_T), observed with clinical features such as cerebellar ataxia, immunodeficiency, occulocutaneous telangiectasia, and sensitivity towards radiation [161]. An impaired ATM gene function produces chromosomal instability, leading to dysfunctional immune response and thus activates systemic inflammatory signaling that participates in the onset of neurodegeneration, speeding up the aging process, tampering the cardiovascular system, and developing autoimmune disease similar to the pathological features of A_T [162].

McGrath-Morrow et al. [163] had identified more than 300 genes expressed in the A_T patients and showed the association of some of the identified genes with the immune/inflammatory pathway when their peripheral blood mononuclear cells were compared with the healthy control (without A_T disease). The authors have also found an increase in the level of IL-8 in serum, uncontrolled/prolonged inflammatory response, and free activation of the innate immune system, indicating the role of inflammation in the A_T pathogenesis; which is more likely to develop in malignancy/death in 4–6 years: yet to be discovered.

Petersen et al. [164] have used flies, with mutated ATM genes, as a model to decipher the mechanism of inflammation-mediated A_T-related neurodegeneration in the brain. Subsequently, the authors have modified the amino-acid in the C-terminal region of the D. melanogaster ATM gene to inhibit the protein kinase activity, and this impaired ATM in the glial cells contributes significantly to sustained immunological responses, which in turn impairs glial mobility or cause glial/neuronal cell death [165]. The authors have also reported that the regulatory molecules (NF-$\kappa$$\beta$ factor) of the IMD pathway, Relish, play a vital role in the onset of neurodegeneration in the glial cells of the ATM mutant flies [164]. Overall, the work on glial cells of ATM mutated D. melanogaster model system decrypted the mechanistic basis of inflammation-mediated A_T-associated neurodegeneration. Although a correlation between inflammation and neurodegeneration is established in the fly model events leading to the unrestricted inflammatory responses in the human A_T patients still needs to be understood.

Traumatic brain injury (TBI) is a consequence of the primary or secondary injuries in the head due to external mechanical forces, which subsequently trigger functional defects in the individual’s behavior, cognition, and physical responses. The severity of the secondary injuries depends on how the host cellular and molecular function responds to the external mechanical stress on the brain primarily [166]. TBI is categorized into subcategories [167], such as (i) based on skull and dura condition; (ii) closed head injuries (no damage observed in dura and skull); (iii) penetrating injuries (damage observed in both dura and skull); (iv) based on the clinical characteristics (v) length and state of consciousness; (vi) incidence of amnesia and (vii) neurological disorders.

Csuka et al. [168] had reported that dysregulation of the innate immune responses via cytokines can stimulate secondary injuries in humans, indicating the role of inflammation in the pathogenesis of TBI. On the contrary, some studies on TBI patients have also reported the beneficial role of cytokines to rescue the neural system [169]. TBI patients are observed with an elevated level of TNF in the CSF which indirectly affects the patient negatively. Thus, targeting TNF serves as a potential therapeutic for TBI treatment [170].

Recently, as D. melanogaster is modeled in various studies related to inflammation and neurodegeneration, Katzenberger et al. [166] developed ‘high-impact trauma’. This adjustable device primarily imposes closed-head TBI conditions in flies. These close head-TBI fly models are found with elevated expression of genes such as ‘metchnikowin’ and ‘spz’ of Toll and IMD pathways, respectively. Consequently, hyper-activated immune pathway has also been reported in the TBI fly model, inducing damage in the neural system similar to that of aged flies undergoing neurodegeneration [171].

Unrestrained AMPs expression leads to neurodegeneration mediated vacuolar lesion formation in the neuropil (area of nervous system comprising dendrites, unmyelinated axons, and glial cells) of the human brain [115]. The vacuolar lesions analogous to the brain are identified in the nervous system (neuropil area) of the flies used as TBI model. These lesions in the TBI Drosophila model vary from as small as 1.0 $\mu$m in diameter to somewhat large. The size variation of the vacuolar lesion depends on the age of the flies [166]. The larger the size of the lesion, the older is the fly. However, the role of varied dimension of these lesions on survivability of the TBI flies or development of neurodegenerative disease/pathologies has not been elucidated yet. Hence, the significance of these vacuolar lesion size variations in the AMP-induced inflammation-mediated TBI neurodegeneration can be studied in the future.