Biology subjects

Vit, J.-P.

Publications and source records attributed to Vit, J.-P..

5 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

Epigenetic derepression of H3K9me3 mitigates Alzheimer-related pathology and improves cognition via immunomodulation and Vgf induction

We investigated the role of histone 3 lysine 9 trimethylation (H3K9me3), an epigenetic mechanism involved in the repression of synaptic plasticity and memory-related genes, within aging and Alzheimers disease (AD). Our study reveals that elevated cortical H3K9me3 strongly correlates with cognitive dysfunction in individuals with mild cognitive impairment (MCI) and AD. In old (18 months) and younger (14 months) APPSWE/PS1{Delta}E9 and 3xTg AD mouse models, inhibiting SUV39H1 methyltransferase with ETP69, substantially reduces cerebral H3K9me3 levels and attenuates amyloid-{beta} burden, tau pathology, and gliosis. Administration of ETP69 further promotes dendritic spine formation, leading to rapid and sustained improvements in cognitive function. Proteomics analysis indicates that a significant proportion of dysregulated proteins in the brains of AD-model mice are reversed by ETP69. These proteins are enriched for synaptic plasticity and learning-related pathways. ETP69 exerts its effects through multiple neuroprotective mechanisms, including regulation of neuroinflammation, induction of both blood and cerebral-infiltrating monocytes involved in cerebral A{beta} clearance. Moreover, ETP69 activates brain-derived neurotrophic factor (Bdnf) network, and particularly its downstream effector neurosecretory protein Vgf. These findings support the pharmacological inhibition of H3K9me3-mediated gene silencing to reverse AD-related pathology and cognitive decline.

neuroscience↗

bioRxiv2021

AAV9-MCT8 delivery at juvenile stage ameliorates neurological and behavioral deficits in an AHDS mouse model

Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. AAV9-based gene therapy is a promising approach to treat monogenic neurological disorders. Here, the potential of this approach was tested in the well-established double knockout (dKO) Mct8-/y;Oatp1c1-/- mouse model of AHDS, which displays disease-relevant neurological and TH phenotypes. Systemic intravenous delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive function, as well as rescue of T3-brain content and T3-related gene expression. This preclinical study indicates that this gene therapy may improve the neurological symptoms of AHDS patients.

neuroscience↗