Synaptic loss correlates with pTau accumulation and decreased UCH-L1 expression in the retinas of MCI and Alzheimer’s patients

Abstract

Purpose : Cerebral hallmarks of Alzheimer’s disease (AD) manifest in the neurosensory retina at early disease stages. However, synaptic loss that tightly predicts cognitive decline has never been described in the AD retina. The ubiquitin-proteasome system (UPS), a major degradation pathway for damaged proteins, has been implicated in AD pathogenesis. A vital component of UPS, ubiquitin hydrolase (UCH-L1), exhibits a neuroprotective role and is required for normal synaptic function. Since low levels of brain UCH-L1 were linked with cerebral Aβ accumulation in AD, we explored its expression in AD patients’ retina.

Methods : Using various histological approaches, we assessed synaptic integrity, tauopathy, apoptosis and UCH-L1 levels in post-mortem retinas of patients with confirmed mild cognitive impairment (MCI) due to AD or AD dementia, compared to age- and sex-matched subjects with normal cognition (NC). We visualized and quantified synaptic density by analysis of pre- and post-synaptic markers (e.g., VGlut1, PSD95, Synaptophysin) and determined their spatial and cell layer distribution.

Results : We detected extensive (1.6- to 3-fold) pre- and post-synaptic losses in the IPL and OPL of MCI and AD patients, whereas early synaptic loss was mostly detected in the far peripheral regions. Along with marked synaptic loss, the retinal layers of MCI and AD patients demonstrated 2- to 4-fold decreases in levels of UCH-L1 as compared to NC. Notably, decreased levels of retinal UCH-L1 directly correlated with pre-synaptic loss (p<0.0001), especially in the far periphery of AD patients. The pre-synaptic VGluT1 marker also inversely correlated with pTau (e.g., AT8) accumulation, colocalizing at sites of synaptic loss, in the IPL and OPL layers in MCI and AD patients. These changes were accompanied by significant 1.8-4.2-fold increases in apoptotic cell death in the retinas of these patients (p< 0.05–0.001).

Conclusions : Our results reveal a substantial retinal synaptic loss at sites of pTau accumulation in prodromal and clinical AD patients. Retinal UCH-L1 expression was significantly deficient in MCI and AD patients, and due to its part in the UPS protein degradation pathway and tight correlation with retinal synaptic loss in AD, this study suggests its importance in retinal synaptic protection against AD-related stress.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.