Spatial interplay between synaptic loss, UCH‐L1 deficiency, and pTau accumulation in the retina of MCI and AD patients

Abstract

AbstractBackgroundSynaptic dysfunction occurs early during Alzheimer’s disease (AD) progression and is considered a strong predictor of cognitive decline. However, it has never been investigated in the AD retina. The ubiquitin‐proteasome system (UPS) is a major degradation pathway for damaged proteins and has been implicated in synaptic integrity and AD pathogenesis. Deficiency in ubiquitin hydrolase (UCH‐L1), a vital UPS component known for its neuroprotective and synaptoprotective properties, was previously linked to cerebral Aβ accumulation in AD, yet has never been explored in the AD retina.MethodWe employed a range of histological techniques to evaluate synaptic integrity and retinal pathology in postmortem retinas of patients with mild cognitive impairment (MCI) attributable to AD or AD dementia, compared to retinas from age‐matched individuals who displayed normal cognition (NC). We assessed the presence of amyloidosis, gliosis, tauopathy, apoptosis, in relation to UCH‐L1 levels, and visualized and quantified synaptic density through analysis of pre‐ and post‐synaptic markers while also assessing the spatial and cellular layer distribution of these markers.ResultWe detected extensive pre‐ and post‐synaptic losses in the IPL and OPL layers of MCI and AD patients, particularly in the far peripheral regions. This was accompanied by 2‐ to 4‐fold decrease in levels of UCH‐L1 in the retinal layers of MCI and AD patients, which directly correlated with pre‐synaptic loss (p<0.0001). These changes were inversely correlated with pTau accumulation (e.g., AT8, pS396), colocalizing at sites of synaptic loss in the IPL and OPL layers. Furthermore, there were significant (1.8‐4.2‐fold) increases in apoptotic cell death in the retinas of these patients (p<0.05–0.001). Remarkably, the pre‐synaptic losses significantly correlated with decreased cognitive scores.ConclusionOur results reveal a substantial retinal synaptic loss at sites of pTau accumulation in prodromal and clinical AD patients. Expression of retinal UCH‐L1 was significantly reduced in MCI and AD patients and strongly associated with synaptic loss and cognitive decline, signifying its potential role in protecting retinal neurons against AD‐related pathology.