Synergistic retinal UCHL1 dysregulation and synaptic vulnerability reflect Alzheimer’s disease severity
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Synaptic failure predicts cognitive decline in Alzheimer's 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-β 42 (Aβ42) and immature tau species, heightened oxidative stress, and upregulation of the Aβ-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 Aβ/p75NTR-mediated UCHL1 imbalance as a proteostasis-synapse mechanistic hub and candidate biomarker reflecting AD severity.
Authors: Altan Rentsendorj, Jean-Philippe Vit, Alexandre Hutton, Yosef Koronyo, Saba Shahin, Edward Robinson, Ernesto Barron, Anthony Rodriguez, Bhakta Prasad Gaire, Ousman Jallow, Julia Sheyn, Miyah Rene Davis, Alexander V. Ljubimov, Stuart L. Graham, Vivek K. Gupta, Mehdi Mirzaei, Debra Hawes, Keith L. Black, Lon S. Schneider, Alfredo A. Sadun, Jesse G. Meyer, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7127942943