Diminished retinal UCH-L1 and synapses in MCI and AD patients strongly links to retinal amyloidosis, tauopathy, and cognitive impairment

Abstract

Purpose : The pathological features of Alzheimer’s disease (AD) extend to the neurosensory retina, an accessible CNS tissue for noninvasive high-resolution imaging in clinical settings. Synaptic dysfunction is an early and strong predictor of cognitive decline. Although the deficiency in ubiquitin hydrolase (UCH-L1), a crucial UPS component with synaptic-protective properties, has been linked to Aβ plaque in AD brains, its presence in the human retina and potential relationship with synaptic and cognitive integrity have yet to be investigated.

Methods : Using histological and mass spectrometry approaches, we assessed pre- and post-synaptic markers, along with UCH-L1 expression, in postmortem retinas from confirmed AD and MCI patients, comparing them to age- and sex-matched subjects with normal cognition (NC). We applied Pearson’s (r) correlation analyses to determine the relationships between amyloidosis, gliosis, tauopathy, apoptosis, and atrophy severity to UCH-L1 and synaptic biomarkers in the retina. These retinal observations were then correlated with AD-related brain parameters and cognitive scores.

Results : We detected marked pre- (VGLUT1: 44%-59%, Synaptophysin: 56%-77%) and post- (PSD95: 44%-66%; NMDAR2: 59%-74%) synaptic losses in the IPL and OPL layers, accompanied by a 43% - 69% decrease in UCH-L1 across the retinal layers of MCI and AD patients. The decreased levels of UCH-L1 were directly and strongly correlated with synaptic losses (p<0.0001). Notably, they were tightly correlated with retinal Aβ₄₂ and pTau accumulation (e.g., pS396, AT8), and remarkably, they were closely linked to the severity of cognitive impairment (e.g., MMSE, CDR).

Conclusions : Our results reveal a substantial loss of retinal synapses at sites of Aβ and pTau accumulation in prodromal and clinical AD patients. The expression of retinal UCH-L1 was significantly reduced in MCI and AD patients, showing a strong association with both synaptic loss and cognitive decline. This signifies its potential role in protecting retinal synapses against AD-related pathology and suggests retinal UCH-L1 as a future retinal biomarker for predicting cognitive decline.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.