Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

• DOI: 10.1007/s00401-024-02760-8
• Publication Date: 2024-07-09T09:02:50Z
• Authors: Haoshen Shi; Nazanin Mirzaei; Yosef Koronyo; Miyah R. Davis; Edward Robinson; Gila M. Braun; Ousman Jallow; Altan Rentsendorj; V. Krishnan Raman...; Justyna Fert-Bober; Andrei A. Kramerov; Alexander V. Ljub...; Lon S. Schneider; Warren G. Tourtel...; Debra Hawes; Julie A. Schneider; Keith L. Black; Rakez Kayed; Maj-Linda B. Sele...; Daniel C. Lee; Dieu-Trang Fuchs; Maya Koronyo-Hamaoui
• Keywords: Tau Pathology; Tau protein; Tangle; Tauopathy

Abstract This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer’s disease (AD), exploring their connection status. Retinal cross-sections from predefined superior-temporal inferior-temporal subregions corresponding brains neuropathologically confirmed AD patients a clinical diagnosis either mild cognitive impairment (MCI) or dementia ( n = 45) were compared retinas age- sex-matched normal cognition 30) non-AD 4). isoforms, including tangles, paired helical filament (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), citrullinated-tau (Cit-tau), stereologically analyzed by immunohistochemistry Nanostring GeoMx digital spatial profiling, correlated neuropathological outcomes. Our data indicated significant increases AD-related pretangle especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR -tau; 4.1-fold), Oligo-tau (T22 + , 9.2-fold), as well mature tangle forms like MC-1-positive (1.8-fold) PHF-tau (2.3-fold), to control retinas. MCI also exhibited substantial (5.2-fold), CitR -tau (3.5-fold), pS396-tau (2.2-fold). analysis elevated retinal epitopes: Ser214 Ser396 (2.6-fold), Ser404 (2.4-fold), Thr231 (1.8-fold), particularly patients. Strong associations found between versus brain pathology status: a) vs. Braak stage, neurofibrillary tangles (NFTs), CDR scores ρ 0.63–0.71), b) neuropil threads (NTs) ABC 0.69–0.71), c) NTs, NFTs, 0.67–0.74). Notably, strongly Aβ 42 arterial 40 r 0.76–0.86). Overall, this identifies quantifies diverse patients, underscoring link cognition. These findings advocate for further exploration tauopathy biomarkers facilitate detection monitoring via noninvasive imaging.