The global spread of microplastics has become a serious public health concern. Once thought to be inert, microplastics are now recognized as biologically active agents capable of accumulating in the body and causing toxic effects across organ systems. This review summarizes current evidence on their oxidative and inflammatory effects in the central nervous system (CNS) and the eye. Studies show that microplastics can cross biological barriers such as the blood-brain barrier (BBB) and blood-retinal barrier (BRB), where they are taken up by cells, impair mitochondria, and trigger inflammation. Microplastics have been found in cerebrospinal fluid, brain tissue, and ocular structures, raising concern about their link to neurodegenerative and retinal diseases, including Alzheimer's, Parkinson's, macular degeneration, and other disorders. Mechanistic data indicate activation of NF-κB and TGF-β1 pathways, promotion of protein aggregation, and disruption of neural signaling. In the eye, microplastics have been linked to oxidative stress, corneal thinning, and photoreceptor damage. However, human studies are limited due to challenges in detecting tiny particles and lack of microplastic-free controls. Research is further hindered by inconsistent definitions, particle diversity, and non-physiological exposure models. We highlight the need for standardized methods, multi-omics tools, and long-term studies to better understand exposure impacts. Given the rise in neurological and ocular diseases, clarifying the role of microplastics is essential for effective public health strategies.

Microglia, Müller cells, and astrocytes play a crucial role in maintaining retinal structure, homeostasis, and neuronal function. In disease, they undergo reprogramming that drives chronic inflammation and neurodegeneration. Unique to the retina, these glial cells occupy specialized niches and interact closely with the blood-retinal barrier, creating distinct vulnerabilities. We summarized the glial activation mechanisms, shared triggers, including oxidative stress, metabolic dysfunction, aging, and systemic inflammation, as well as key pathways, such as nuclear factor kappa-B, mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription, the inflammasome, and the complement system. Disease-specific responses in glaucoma, age-related macular degeneration, diabetic retinopathy, and vascular occlusions were compared, highlighting the heterogeneity of gliosis and its impact on neuronal and vascular pathology. We also discussed emerging human-derived platforms alongside proteomics approaches, highlighting their utility for mechanistic insights and discovering biomarkers. Despite advances, critical gaps remain in understanding glial-glial interactions and in developing robust models focused on glia. Despite these advances, major gaps remain in our understanding of glial-glial communication, state transitions, and their temporal relationship to neurodegeneration. Moreover, the lack of experimental models explicitly designed to interrogate glial biology continues to limit translational progress. Addressing these challenges will be essential to reposition glial cells as central drivers of retinal disease rather than secondary responders. A strategic shift toward glia-centered models, integrative multi-omics analyses, and human-relevant systems holds promise for advancing biomarker discovery and developing targeted therapeutic strategies that aim to modulate glial dysfunction and preserve vision.

Neuropeptide Y (NPY) is a multifunctional peptide with neuroprotective properties, but its therapeutic use in the retina and optic nerve may be limited by vasoconstrictive effects mediated through Y1 receptor activation. This study evaluated the vascular effects of full-length NPY (1-36) and its N-terminally truncated analog, NPY (3-36), in the mouse retina. Retinal vascular responses were assessed using fluorescein angiography (FFA) after intravitreal administration of different NPY analogs. NPY (1-36) caused transient vasoconstriction via Y1 receptor-mediated calmodulin and pMLC activation. In contrast, NPY (3-36) selectively activates Y2 and Y5 receptors without inducing vasoconstrictive effects. Furthermore, NPY (3-36) through receptor activation preserved retinal ganglion cell density, axonal integrity, and inner retinal function while reducing astrocytic and microglial activation under elevated intraocular pressure. These findings suggest that NPY (3-36) could be a safer therapeutic candidate for glaucoma, highlighting the critical role of receptor-specific modulation to enhance neuroprotection without causing adverse vascular complications.

Glaucoma, a leading cause of irreversible blindness, is characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve damage, often associated with elevated intraocular pressure (IOP). Retinoid X receptors (RXRs) are ligand-activated transcription factors crucial for neuroprotection, as they regulate gene expression to promote neuronal survival via several biochemical networks and reduce neuroinflammation. This study investigated the therapeutic potential of 9-cis-13,14-dihydroretinoic acid (9CDHRA), an endogenous retinoid RXR agonist, in mitigating RGC degeneration in a high-IOP-induced experimental model of glaucoma. We administered 9CDHRA to glaucomatous mice eyes via intravitreal injections and assessed its effects on endoplasmic reticulum (ER) stress markers, glial cell activation, and RGC survival. Our findings demonstrated that 9CDHRA treatment significantly protected inner retinal function and retinal laminar structure in high-IOP glaucoma. The treatment reduced ER stress markers, increased protein lysine acetylation, and diminished glial cell activation, leading to a significant decrease in apoptotic cells under glaucomatous conditions. These results suggest that 9CDHRA exerts neuroprotective effects by modulating key pathogenic pathways in glaucoma, highlighting its potential as a novel therapeutic strategy for preserving vision in glaucoma.

Glaucoma is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve head (ONH) changes, but the roles of glial activation and immune responses remain unclear. This study examines gliosis, microglial diversity, and inflammation in postmortem retinal tissues. Postmortem retinal and ONH samples (total n = 50) from patients with open-angle glaucoma (G, n = 18) were compared with those from age-matched controls (n = 32), including healthy individuals (Ctrl) and disease controls (patients with early age-related macular degeneration [AMD] and diabetes mellitus [DM]). Immunostaining was performed to assess glial activation, blood–retinal barrier (BRB) integrity, and immune infiltration, which were quantified via ImageJ and Zen lite. Generalized estimating equations (GEEs) with Bonferroni correction accounted for intrapatient variability. G retinae presented significant RGC loss accompanied by widespread gliosis, with activation of microglia (Iba1), astrocytes (GFAP), and Müller cells (Vimentin). This gliotic response differed across conditions, with astrocyte activation being more prominent in DM and microglial activation predominating in AMD. In glaucoma, gliosis is evident even in early-stage disease, regardless of the severity of retinal ganglion cell (RGC) loss or structural changes in the ONH. Furthermore, microglia showed a marked shift in morphological diversity, transitioning to hyperramified, bushy, and amoeboid forms, along with an increased distribution of activation markers such as CD45, CD11b, and CD163. Additionally, biochemical evidence of alterations to the BRB integrity, characterized by reduced tight junction protein expression, facilitates immune cell infiltration, as indicated by the minimal and inconsistent presence of CD3/CD4+ T cells. Gliosis persisted regardless of RGC loss severity, suggesting that gliosis progresses independently of neuronal degeneration. Unlike AMD and DM, where specific glial subtypes dominate, glaucoma exhibits widespread gliosis. Microglial heterogeneity indicates the existence of a continuum of functional states. Furthermore, dysregulation of the BRB, inconsistent immune infiltration, and multimodal microglial activation indicate that the inflammatory response in glaucoma patients is driven primarily by resident microglia, with limited interactions with infiltrating immune cells. These findings highlight the need for further research into glial modulation as a potential therapeutic strategy.

Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve axons, and its risk increases with age. Retinal neuroinflammation and epigenetic changes have been suggested to be key contributors to glaucoma neuropathology. Recent research suggests that activating the retinoid X receptor (RXR) in the retina plays a critical role in modulating various cellular functions, showcasing beneficial effects in animal models of glaucoma. Yet, the neuroprotective mechanisms activated in response to RXR modulation in glaucoma remain unclear. This study investigated the impact of RXR alpha (RXRα) modulation on retinal neurons in vivo under both normal and glaucoma conditions using adeno-associated virus (AAV) gene therapy. RXRα knockdown in RGCs promoted histone deacetylation, pro-inflammatory, and apoptotic changes, along with inducing functional and structural deficits in the inner retina. In contrast, overexpression of RXRα in RGCs protected these cells and preserved inner retinal function in glaucoma through the activation of PI3K/Akt/Gsk3β signaling. This study identified the RXRα-mediated epigenetic and inflammatory regulatory mechanisms in RGCs and established that specifically targeting RXRα in RGCs imparts functional and cellular protection to the retina in glaucoma, with potential implications in other neurodegenerative disorders.

The repressor element 1-silencing transcription factor (REST), or neuron-restrictive silencer factor (NRSF), is crucial for gene regulation since it binds to chromatin and recruits chromatin-modifying enzymes. Acting as a regulatory hub, REST orchestrates neurogenesis, neuronal differentiation, and the preservation of neuronal identity by regulating a broad network of target genes across stem cells, non-neuronal cells, and neurons. These targets influence critical processes such as axonal growth, vesicular transport, neurotransmitter release, and ion conductance. An important feature of normal aging in cortical and hippocampal neurons is REST induction, where it contributes to extended longevity by repressing genes linked to neuronal excitability and stress vulnerability. However, REST's role in neurodegenerative diseases remains complex and context dependent. Variations in its expression and subcellular localization, including cytoplasmic translocation or loss, have been implicated in the pathology of disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and epilepsy. Given its broad regulatory functions, REST has emerged as an attractive therapeutic target. Strategies such as microRNA modulation, small molecule inhibitors, and complex-disrupting compounds have been explored, each offering unique opportunities and challenges. Understanding REST's molecular mechanisms and disease-specific functions is critical for identifying novel therapeutic interventions. This review provides a comprehensive analysis of REST's role in aging and neurodegeneration, highlighting its regulatory networks, disease relevance, and recent therapeutic strategies targeting REST, with an emphasis on their potential for clinical translation.

Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.

The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.

Neural regeneration and neuroprotection represent strategies for future management of neurodegenerative disorders such as Alzheimer’s disease (AD) or glaucoma. However, the complex molecular mechanisms that are involved in neuroprotection are not clearly understood. A promising candidate that maintains neuroprotective signaling networks is neuroserpin (Serpini1), a serine protease inhibitor expressed in neurons which selectively inhibits extracellular tissue-type plasminogen activator (tPA)/plasmin and plays a neuroprotective role during ischemic brain injury. Abnormal function of this protein has been implicated in several conditions including stroke, glaucoma, AD, and familial encephalopathy with neuroserpin inclusion bodies (FENIB). Here, we explore the potential biochemical roles of Serpini1 by comparing proteome changes between neuroserpin-deficient (NS−/−) and control mice, in the retina (RE), optic nerve (ON), frontal cortex (FC), visual cortex (VC), and cerebellum (CB). To achieve this, a multiple-plex quantitative proteomics approach using isobaric tandem mass tag (TMT) technology was employed followed by functional enrichment and protein–protein interaction analysis. We detected around 5000 proteins in each tissue and a pool of 6432 quantified proteins across all regions, resulting in a pool of 1235 differentially expressed proteins (DEPs). Principal component analysis and hierarchical clustering highlighted similarities and differences in the retina compared to various brain regions, as well as differentiating NS−/− proteome signatures from control samples. The visual cortex revealed the highest number of DEPs, followed by cerebellar regions. Pathway analysis unveiled region-specific changes, including visual perception, focal adhesion, apoptosis, glutamate receptor activation, and supramolecular fiber organization in RE, ON, FC, VC, and CB, respectively. These novel findings provide comprehensive insights into the region-specific networking of Serpini1 in the central nervous system, further characterizing its potential role as a neuroprotective agent. Data are available via ProteomeXchange with identifier PXD046873.

Abstract Myelination of axons in the central nervous system offers numerous advantages, including decreased energy expenditure for signal transmission and enhanced signal speed. The myelin sheaths surrounding an axon consist of a multi-layered membrane that is formed by oligodendrocytes, while specific glycoproteins and lipids play various roles in this formation process. As beneficial as myelin can be, its dysregulation and degeneration can prove detrimental. Inflammation, oxidative stress, and changes in cellular metabolism and the extracellular matrix can lead to demyelination of these axons. These factors are hallmark characteristics of certain demyelinating diseases including multiple sclerosis. The effects of demyelination are also implicated in primary degeneration in diseases such as glaucoma and Alzheimer’s disease, as well as in processes of secondary degeneration. This reveals a relationship between myelin and secondary processes of neurodegeneration, including resultant degeneration following traumatic injury and transsynaptic degeneration. The role of myelin in primary and secondary degeneration is also of interest in the exploration of strategies and targets for remyelination, including the use of anti-inflammatory molecules or nanoparticles to deliver drugs. Although the use of these methods in animal models of diseases have shown to be effective in promoting remyelination, very few clinical trials in patients have met primary end points. This may be due to shortcomings or considerations that are not met while designing a clinical trial that targets remyelination. Potential solutions include diversifying disease targets and requiring concomitant interventions to promote rehabilitation.

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.

Purpose: Neuropeptide Y (NPY) is an endogenous 36‐amino acid linear peptide with tyrosine residues on both ends of the molecule. Cumulative evidence suggests that NPY and its receptors in the CNS may be a potential neuroprotective targets in various degenerative conditions. This study aimed to investigate the protective effects of NPY in the retina in an experimentally induced glaucoma animal model. Methods: Weekly intracameral microbead injections were performed to induce sustainably increased intraocular pressure (IOP) and NPY was administered intravitreally for 2 months. Wild‐type C57BL/6J mice ( n = 40) were categorized into four major groups i) control, ii) control + NPY, iii) high IOP model, & iv) high IOP + NPY. Inner retinal function was evaluated by using positive scotopic threshold response (pSTR) amplitudes. Eye and optic nerve sections were then immunostained with pNFH (phosphorylated neurofilament heavy chain), GFAP (glial fibrillary acidic protein) and Iba‐1(Ionized calcium‐binding adaptor molecule 1) antibodies to understand the protective effects of NPY treatment. Results: IOP elevation was observed in the microbead model (control, 10.5 ± 0.75; microbead, 27.35 ± 1.92 mmHg). Functional data revealed a significant decline in the pSTR amplitudes in high IOP conditions ( p < 0.0001, n = 10) compared to the control group, and a significant increase in pSTR was observed in the high IOP + NPY group ( p < 0.001, n = 10). Optic nerves stained with pNFH revealed a significant protective effect of NPY treatment against high IOP‐induced axonal damage ( p < 0.01, n = 4). Increased GFAP expression observed in high IOP condition was significantly decreased with NPY treatment both in the retina ( p < 0.001, n = 4) and optic nerves ( p < 0.01, n = 4). Similarly, microglial activation evaluated by Iba‐1 expression was also significantly decreased by NPY treatment both in the retina ( p < 0.01, n = 4) and optic nerves ( p < 0.01, n = 4). Conclusions: NPY treatment significantly reduced inner retinal functional loss and optic nerve damage against high IOP‐induced glaucomatous injury. NPY also reduced the microglial activation and reactive gliosis in experimental glaucoma. Our ongoing investigation will reveal specific NPY receptors activation and biochemical mechanism underlying these protective effects in the retina.

P URPOSE . Remyelination therapies are advancing for multiple sclerosis, focusing on visual pathways and using visual evoked potentials (VEPs) for de/remyelination processes. While the cuprizone (CZ) model and VEPs are core tools in preclinical trials, many overlook the posterior visual pathway. This study aimed to assess functional and structural changes across the murine visual pathway during de/remyelination. M ETHODS . One group of C57BL/6 mice underwent a CZ diet for 6 weeks to simulate demyelination, with a subset returning to a regular diet to induce remyelination. An additional group was fed a protracted CZ diet for 12 weeks to maintain chronic demyelination. Visual function was evaluated using electrophysiological recordings, including scotopic threshold responses (STRs) and electroretinograms (ERGs), with VEPs serving as a key biomarker for overall pathway health. Tissues from eyes, brains, and optic nerves (ONs) were collected at different time points for structural analysis. R ESULTS . Our results demonstrated significant effects on VEPs, including increased N1 latencies and reduced amplitudes in the CZ mouse model. However, retinal function remained unaffected, as evidenced by unchanged STRs, ERGs, and retinal ganglion cell counts. Analysis of ONs revealed morphological changes, characterized by a significantly decreased axon diameter in the core region compared to the subpial region. Additionally, there was a significant increase in the g-ratio of the core region at 12 weeks CZ compared to controls. Immunofluorescence further demonstrated a decrease in myelin basic protein levels at 6 and 12 weeks in CZ animals. Interestingly, the dorsal lateral geniculate nucleus and primary visual cortex (V1) exhibited similar myelin changes, correlating with VEP latency alterations. C ONCLUSIONS . These data reveal that interpreting VEP latency solely as a marker for ON demyelination is incomplete. Previous preclinical studies have overlooked the posterior visual pathways, necessitating a broader interpretation of VEP latency to cover the entire visual pathway.

Neurodegenerative and demyelinating disease, such as multiple sclerosis (MS) are at the forefront of medical research and the discovery of new drugs and therapeutics. One phenomenon of degeneration seen in these diseases is transsynaptic degeneration (TSD), where damage from one axon spreads to the other axons that are connected to it synaptically. It has previously been found that demyelination occurs prior to neuronal loss in an experimental form of induced TSD. Retinoid-x receptor (RXR) agonists have been shown to promote remyelination. Therefore, this study aimed to reveal the effects of a novel endogenous RXR-γ agonist, 9-cis-13,14-dihydroretinoic acid (9CDHRA), on preventing or restoring the effects of TSD. 9CDHRA was administered to mice following optic nerve crush (ONC) procedures, and electrophysiology (visual evoked potential, VEP) and histological (immunofluorescent) assessments were performed. It was found that 9CDHRA treatment effectively delayed glial activation and reduced the presence of apoptosis at the site of injury and further anterogradely in the visual system, including the lateral geniculate nucleus (LGN) and primary visual cortex (V1). Most notably, 9CDHRA was able to maintain myelin levels following ONC, and effectively protected from demyelination. This was corroborated by VEP recordings with improved P1 latency. The promising findings regarding the injury attenuating and myelin protecting properties of 9CDHRA necessitates further investigations into the potential therapeutic uses of this compound.

Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised. This review provides a comprehensive summary of neuroinflammatory responses in glaucoma. A systematic search of Medline and Embase for articles published up to 8th March 2023 yielded 32 studies using post-mortem tissues from glaucoma patients. The raw data were extracted from tables and text to calculate the standardized mean differences (SMDs). These studies utilized post-mortem tissues from glaucoma patients, totalling 490 samples, compared with 380 control samples. Among the included studies, 27 reported glial cell activation based on changes to cellular morphology and molecular staining. Molecular changes were predominantly attributed to astrocytes (62.5%) and microglia (15.6%), with some involvement of Muller cells. These glial cell changes included amoeboid microglial cells with increased CD45 or HLA-DR intensity and hypertrophied astrocytes with increased glial fibrillary acidic protein labelling. Further, changes to extracellular matrix proteins like collagen, galectin, and tenascin-C suggested glial cells' influence on structural changes in the optic nerve head. The activation of DAMPs-driven immune response and the classical complement cascade was reported and found to be associated with activated glial cells in glaucomatous tissue. Increased pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also linked to glial cells. Glial cell activation was also associated with mitochondrial, vascular, metabolic and antioxidant component disruptions. Association of the activated glial cells with pro-inflammatory responses, dysregulation of homeostatic components and antigen presentation indicates that glial cell responses influence glaucoma progression. However, the exact mechanism triggering these responses and underlying interactions remains unexplored. This necessitates further research using human samples for an increased understanding of the precise role of neuroinflammation in glaucoma progression.

Neuropeptide Y (NPY), an endogenous peptide composed of 36 amino acids, has been investigated as a potential therapeutic agent for neurodegenerative diseases due to its neuroprotective attributes. This study investigated the neuroprotective effects of NPY in a mouse model of glaucoma characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell degeneration. Elevated IOP in mice was induced through intracameral microbead injections, accompanied by intravitreal administration of NPY peptide. The results demonstrated that NPY treatment preserved both the structural and functional integrity of the inner retina and mitigated axonal damage and degenerative changes in the optic nerve under high IOP conditions. Further, NPY treatment effectively reduced inflammatory glial cell activation, as evidenced by decreased expression of glial fibrillary acidic protein and Iba-1. Notably, endogenous NPY expression and its receptors (NPY-Y1R and NPY-Y4R) levels were negatively affected in the retina under elevated IOP conditions. NPY treatment restored these changes to a significant extent. Molecular analysis revealed that NPY mediates its protective effects through the mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling pathways. These findings highlight the therapeutic potential of NPY in glaucoma treatment, underscoring its capacity to preserve retinal health, modulate receptor expression under stress, reduce neuroinflammation, and impart protection against axonal impairment.

A prominent feature in many neurodegenerative diseases involves the spread of the pathology from the initial site of damage to anatomically and functionally connected regions of the central nervous system (CNS), referred to as transsynaptic degeneration (TSD). This review covers the possible mechanisms of both retrograde and anterograde TSD in various age-related neurodegenerative diseases, including synaptically and glial mediated changes contributing to TDS and their potential as therapeutic targets. This phenomenon is well documented in clinical and experimental studies spanning various neurodegenerative diseases and their respective models, with a significant emphasis on the visual pathway, to be explored herein. With the increase in the aging population and subsequent rise in age-related neurodegenerative diseases, it is crucial to understand the underlying mechanisms of.