Identification of diverse pathological Tau forms in the retina of MCI and AD patients

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Abstract Background Neurofibrillary tangles (NFTs) formed by abnormal accumulation of the microtubule‐associated protein tau is a key pathological hallmark of Alzheimer’s disease (AD). Presence of abnormal tau forms has been shown to correlate with the degree of neurodegeneration and cognitive decline. A few studies have previously described increases of hyperphosphorylated tau (pTau) in postmortem retinas of AD patients. However, it remains largely unknown if these and other abnormal tau forms are present in the retina of mild cognitively impaired (MCI) and AD patients and their relations with brain pathology is undefined. Method Fifty‐three postmortem human eyes and thirty‐nine paired brains were obtained for this study. Retinas were isolated from 22 AD and 10 MCI patients, and 21 age‐ and sex‐matched cognitively normal (CN) controls. Retinal cross‐sections spanning along ora serrata to optic disc were prepared from four pre‐defined quadrants: superiortemporal, temporalinferior, inferiornasal, and nasalsuperior. Histological analyses were conducted by immunostaining brain and retinal cross‐sections by specific antibodies for NFTs and oligomeric Tau. pTau were explored by using antibodies to detect pS396+, AT8+ (Ser202, Thr205) and AT100+ (Thr212, Ser214). Quantification of tauopathy forms were measured by stereological examination then correlated with the neuropathological reports of these patients. Result Our examination by both immunofluorescence and peroxidase‐based staining identified the presence of NFTs and novel oligomeric tau forms in AD‐afflicted retina. Stereological analyses of retinal cross‐sections and brains demonstrated a significant upregulation of NFTs and AT8+, pS396+ pTau forms in retinas from MCI patients compared to CN controls; exacerbated tauopathy was found in the retina of AD patients. NFTs and pTau were more frequent in the peripheral retina compared with the central retina. We found intense staining patterns of tauopathy along the synaptic‐rich regions (OPL and IPL). Preliminary correlation analysis suggest significant associations between retinal pS396+ pTau burden and cerebral pathologies including NFT burden, neuropil threads, and cognitive deficit. Conclusion This study identifies NFTs in the AD retina and demonstrates the accumulation of both soluble and fibrillar forms of tauopathy in the retina of MCI and AD patients. Future retinal imaging of tauopathy may allow a noninvasive means to screen and monitor AD progression.

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