Work

Deletion of the N ‐ and C‐termini of tau initiates its aggregation and acquires proteopathic properties

Year: 2025

Type: article

Abstract: Background Intracellular neurofibrillary tangles (NFTs) consisting of aggregated and hyperphosphorylated tau is a major pathological hallmark of Alzheimer's disease and related tauopathies. In AD brain, tau pathology spreads through prion‐like propagation and follows a stereotypical pattern: it originates from the locus coeruleus and transentorhinal cortex (Braak stages I–II), then spreads to the limbic system (Braak stages III–IV), and eventually to the neocortex (Braak stages V–VI). Normally, the acidic N ‐ and C‐termini of tau prefers to fold over the basic microtubule binding repeats (MTBR) to form a paperclip‐like conformation, preventing the protein from self‐aggregation. In AD brain, the extreme N ‐terminus of tau is lost from NFTs and C‐terminal truncations are found in PHFs as well as mature and ghost tangles. Loss of the N ‐ and C‐termini of tau may facilitate self‐aggregation and drive tau pathogenesis. Method A truncated form of tau, tau 151‐391 was generated by deleting the acidic N ‐ and C‐termini of tau and overexpressed in HEK‐293T cells. RIPA buffer insoluble tau 151‐391 aggregates were obtained by ultracentrifugation. Its phosphorylation and proteopathic properties were determined in vitro and in vivo . Result We found that tau 151‐391 , but not full‐length tau (tau FL ), can form aggregates in cultured cells and in vivo in mouse brain. Aggregated tau 151‐391 is hyperphosphorylated at multiple sites, including Thr181, Ser199, AT8, Thr212, Ser214, Thr217, and Thr231, and is partially resistant to hydrolysis by proteinase K. Tau 151‐391 aggregates potently induce tau aggregation and site‐specific hyperphosphorylation in cultured cells and in mouse brain. By repeatedly inducing aggregation in cultured cells, aggregated tau increases exponentially. The seeding activity of tau 151‐391 aggregates is sensitive to repeated freezing and thawing. 3R‐tau 151‐391 , which contains three MTBRs, and 4R‐tau 151‐391 , which contains four MTBRs, can be induced to aggregate by each other's aggregates. Conclusion Deletion of the acidic N ‐ and C‐termini facilitates tau aggregation and acquires proteopathic properties. Tau 151‐391 aggregates effectively induce tau aggregation and site‐specific hyperphosphorylation in cultured cells and in vivo in mouse brain.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70855_107182