Diminished Retinal UCH-L1 Expression Correlates with Synaptic Loss and Cognitive Deficit in Mild Cognitive Impairment and Alzheimer's Disease Patients

Abstract

Purpose : This study examined Ubiquitin hydrolase (UCH-L1), a vital component of the ubiquitin-proteasome system (UPS), expression patterns in the retina of post-mortem human brains from patients with AD dementia and mild cognitive impairment (MCI) due to AD. Growing evidence suggests that UCH-L1 has a neuroprotective role and is essential for normal synaptic function. However, its presence and potential relations to synaptic loss and cognitive deficit that can predict functional decline have yet to be described in the AD retina.

Methods : Using histological approaches, we assessed pre- and post-synaptic marker density and UCH-L1 immunoreactivity in post-mortem retinas of patients with confirmed AD and MCI due to AD and compared them to age-and sex-matched subjects with normal cognition (NC). We also correlated these observations with their respective MMSE scores.

Results : The retina of MCI and AD patients exhibited thinning along with extensive reductions in pre- and post-synaptic markers in the inner and outer plexiform layers (IPL and OPL), which were more pronounced in the retinal mid- and far-peripheral regions. Along with retinal atrophy and severe synaptic losses, we found reductions in levels of UCH-L1 expression in these patients as compared to NC. Notably, retinal UCH-L1 depletion directly and very strongly correlated with pre- and post-synaptic loss. Furthermore, UCH-L1 depletion in the Human Retina was associated with lower MMSE scores.

Conclusions : Our results reveal a substantial retinal synaptic loss in prodromal and clinical AD patients, which was associated with UCH-L1 depletion along with lower cognitive performance. Taken together, these findings suggest that UCH-L1 deficiency may contribute to retinal synaptic dysfunction and vision loss early in AD progression offering a potential target for its diagnosis and treatment.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.