Self-aggregating Tau Fragments Recapitulate Pathologic Phenotypes and Neurotoxicity of Alzheimer's Disease in Mice

In tauopathic conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process are not clear. In AD brains, only a small segment of tau forms -helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, we demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) showed markedly reduced aggregation and seeding propensities. Biophysical analysis revealed that the N-terminus of tau-AC facilitated the fibrillization kinetics, while its phosphorylation induced conformation changes, sterically shielding the nucleation motif. Tau-AC oligomers were efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and was mislocalized in the somatodendritic compartments. Furthermore, we observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponded to the neuropathological staining and neuronal loss in the brain. These findings identified tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.