Retinal tauopathy colocalizes in sites of synaptic loss in patients with mild cognitive impairment and Alzheimer’s disease

Abstract

Purpose : Mounting evidence suggests that Alzheimer’s disease (AD) neuropathological changes are also present in the retinae of patients. These include the proteinaceous accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (pTau) assemblies, gliosis, vascular abnormalities, pericyte loss, and neurodegeneration. Electroretinogram and visual deficits, likely driven by these retinal pathologies, are also documented. Among the main neuropathological hallmarks of AD, tauopathy remains considerably understudied in the retina. Given that cerebral tauopathy is closely linked to neuronal loss and the severity of cognitive deficits in AD patients, it is possible that similar relations exist in the retina between pathologic tau burden, synaptic loss, and neurodegeneration. These may serve as biomarkers of not only retino-visual irregularities but also brain disease and cognitive status.

Methods : Here, using immunohistochemical approaches we visualized and quantified the spatial burden of various AD-related tau species, including pTau, oligomeric and citrullinated tau, and neurofibrillary tangles (NFTs) in the central and peripheral regions of post-mortem retinae from mild cognitive impairment (MCI) and AD patients, relative to cognitively normal controls (NC). Levels of synaptic biomarkers in the retina, as well as the thickness of retinal layers, were also measured in the same cohort of human donors.

Results : Elevated levels of various pTau sites were found in a geometric-dependent manner in the retinae of MCI and AD patients compared to NC. Increased burden of NFTs and citrullinated tau were also identified in retinal layers that were associated with higher retinal synaptic loss and neuronal atrophy. Investigations of retinal cell type susceptibility to tauopathy, including oligomeric tau accumulation in early and late disease stages, reveals the vulnerability of certain retinal neurons in MCI and AD patients.

Conclusions : To date, our results provide new evidence for the presence of AD-specific tauopathy and related synaptic loss as well as neuronal-specific susceptibility in the AD retina, similar to those observed in the brain.

This is a 2021 ARVO Annual Meeting abstract.