Tau oligomer pathology in nucleus basalis neurons during the progression of Alzheimer Disease

Abstract

Although tau is the primary constituent of neurofibrillary tangles (NFTs), evidence suggests that its toxic moiety is oligomeric in Alzheimer disease (AD). In this regard, tau oligomers correlate more strongly with neuronal loss than NFTs and exhibit neurotoxicity in preclinical AD models. Here, we investigated the spatiotemporal progression of oligomeric tau accumulation within the highly vulnerable cholinergic neurons of the nucleus basalis of Meynert (nbM) in AD. Tissue from subjects who died with a clinical diagnosis of no cognitive impairment, mild cognitive impairment, or AD was immunostained with the tau oligomeric complex 1 (TOC1) antibody, a marker of tau oligomers, and p75NTR, a cholinergic cell marker. Stereological estimates revealed a significant increase in the number of TOC1 nbM immunopositive (+) neurons with a concomitant decrease in p75NTR+nbM neurons during the transition from mild cognitive impairment to AD. Immunofluorescence identified TOC1+neurons that colocalized with the pretangle tau marker phospho-Ser422, which persisted into late stage NFTs immunoreactive for MN423. Analysis of the nbM subfields revealed a topographical caudal to rostral gradient of TOC1+neurons during disease progression. Taken together, these data suggest that toxic tau oligomers accumulate caudorostrally in selectively vulnerable nbM neurons during the onset of AD.