Biology subjects

Gaire, B. P.

Publications and source records attributed to Gaire, B. P..

4 recordsLinked to original sources

bioRxiv2026

Sex-specific retina-brain signatures link ERα/ERβ imbalance with gliosis in Alzheimer's disease

Women face a twofold higher lifetime risk of Alzheimers disease (AD) than men, yet the mechanisms underlying female-biased vulnerability and sex-specific disease signatures across the retina-brain axis remain unknown. By integrating clinicopathological and proteomic datasets from paired retinal and brain tissues from 182 donors, we identified sex-divergent molecular and pathological features across the AD continuum. Despite comparable retinal and cerebral amyloid and tau burdens between sexes, females exhibited a more severe neuroinflammatory-neurodegenerative phenotype with intensified gliosis and tissue atrophy, whereas males displayed a dominant vasculopathy, marked by increased retinal vascular A{beta}40 deposition, tight-junction disruption, and cerebral amyloid angiopathy. In females, this profile coincided with inflammation-associated estrogen receptor (ER)- remodeling and reduced global and astrocytic-nuclear ER-{beta}, which associated more strongly with cognitive decline than in males. These results indicate that comparable AD proteinopathy is associated with divergent downstream consequences across the retina-brain axis and identify astrocytic ER/ER{beta} imbalance as a sex-linked glial mechanism associated with female vulnerability in AD.

neuroscience↗

bioRxiv2026

Synergistic retinal UCHL1 dysregulation and synaptic vulnerability reflect Alzheimer's disease severity

Synaptic failure predicts cognitive decline in Alzheimers disease (AD), yet its impact and molecular drivers in the human retina remain unclear. Leveraging the retina as an accessible central nervous system (CNS) proxy, we integrated spatially resolved histopathology of retinal cross-sections with ultrastructural, proteomic, and biochemical profiling across independent postmortem cohorts spanning normal cognition, mild cognitive impairment due to AD (MCI), and AD dementia. We uncover early, progressive degeneration of excitatory glutamatergic synapses, evidenced by losses of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin, and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), accompanied by disruption of synaptic ultrastructure. Retinal synaptic loss tightly associates with local accumulation of amyloid-{beta} 42 (A{beta}42) and immature tau species, heightened oxidative stress, and upregulation of the A{beta}-binding death receptor p75 neurotrophin receptor (p75NTR). Notably, the synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) is profoundly dysregulated, correlates with synaptic integrity and cognition, and emerges as the strongest retinal predictor of Braak stage and cognitive status in multivariable machine-learning models. Together, these findings position retinal A{beta}/p75NTR-mediated UCHL1 imbalance as a proteostasis-synapse mechanistic hub and candidate biomarker reflecting AD severity.

neuroscience↗

bioRxiv2025

Identification of Chlamydia pneumoniae and NLRP3 inflammasome activation in Alzheimer's disease retina

Chlamydia pneumoniae (Cp), an obligate intracellular bacterium, has been implicated in Alzheimers disease (AD), yet its role in retinal pathology remains unexplored. We analyzed postmortem tissues from 95 human donors and found 2.9-4.1-fold increases in Cp inclusions in AD retinas and brains, with no significant elevation in mild cognitive impairment (MCI). Proteomics revealed dysregulation of retinal and brain bacterial infection-related proteins and NLRP3 inflammasome pathways. NLRP3 expression was markedly elevated in MCI and AD retinas, and its activation was evident by increased N-terminal gasdermin D (NGSDMD) and mature interleukin-1{beta}. Retinal Cp strongly correlated with A{beta}42 and NLRP3 inflammasome components, which tightly linked to cleaved caspase-3-apoptotic and NGSDMD-pyroptotic cell death. Although retinal microgliosis was elevated in AD, Cp-associated microglia were reduced by 62%, suggesting impaired Cp phagocytosis. Higher retinal Cp burden correlated with APOE{varepsilon}4, Braak stage, and cognitive deficit. Machine learning identified retinal Cp or NLRP3 combined with A{beta}42 as strong predictors of AD diagnosis, staging, and cognitive impairment. Our findings suggest that Cp infection contributes to AD dementia but not initiating pathology, whereas early NLRP3 activation may promote disease development, warranting studies on Cps role in AD pathogenesis and early antibiotic or inflammasome-targeted therapies.

neuroscience↗

bioRxiv2024

Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease

Accumulation of pathological tau isoforms, especially hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers, has been demonstrated in the retinas of patients with mild cognitive impairment (MCI) and Alzheimers disease (AD). Previous studies have noted a decrease in retinal ganglion cells (RGCs) in AD patients, but the presence and impact of pathological tau isoforms in RGCs and RGC integrity, particularly in early AD stages, have not been explored. To investigate this, we examined retinal superior temporal cross-sections from 25 patients with MCI (due to AD) or AD dementia and 16 cognitively normal (CN) controls, matched for age and gender. We utilized the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining to assess neuronal density in the ganglion cell layer (GCL). Our study found that hypertrophic RGCs containing pS396-tau and T22-positive tau oligomers were more frequently observed in MCI and AD patients compared to CN subjects. Quantitative analyses indicated a decline in RGC integrity, with 46-55% and 55-56% reductions of RBPMS+ RGCs (P<0.01) and Nissl+ GCL neurons (P<0.01-0.001), respectively, in MCI and AD patients. This decrease in RGC count was accompanied by increases in necroptotic-like morphology and the cleaved caspase-3 apoptotic marker in RGCs of AD patients. Furthermore, there was a 2.1 to 3.1-fold increase (P<0.05-0.0001) in pS396-tau-laden RGCs in MCI and AD patients, with a greater abundance observed in individuals with higher Braak stages (V-VI), more severe clinical dementia ratings (CDR=3), and lower mini-mental state examination (MMSE) scores. Strong correlations were noted between the decline in RGCs and the total amount of retinal pS396-tau and pS396-tau+ RGCs, with pS396-tau+ RGC counts correlating significantly with brain neurofibrillary tangle scores (r= 0.71, P= 0.0001), Braak stage (r= 0.65, P= 0.0009), and MMSE scores (r= -0.76, P= 0.0004). These findings suggest that retinal tauopathy, characterized by pS396-tau and oligomeric tau in hypertrophic RGCs, is associated with and may contribute to RGC degeneration in AD. Future research should validate these findings in larger cohorts and explore noninvasive retinal imaging techniques that target tau pathology in RGCs to improve AD detection and monitor disease progression.

pathology↗