Abstract
Accumulation of intracellular neurofibrillary tangles (NFTs), which are constituted of abnormally phosphorylated tau, is one of the neuropathological hallmarks of Alzheimer’s disease (AD). The oligomeric aggregates of tau in AD brain (AD O-tau) are believed to trigger NFT spreading by seeding normal tau aggregation as toxic seeds, in a prion-like fashion. Here, we revealed the features of AD O-tau by Western blots using antibodies against various epitopes and determined the effect of dephosphorylation on the seeding activity of AD O-tau by capture and seeded aggregation assays. We found that N-terminal truncated and C-terminalhyperphosphorylated tau species were enriched in AD O-tau. Dephosphorylation of AD O-tau by alkaline phosphatasediminished its activity in capturing tau in vitro and ininducing insoluble aggregates in cultured cells. Our resultssuggested that dephosphorylation passivated the seeding activity ofAD O-tau. Inhibition of phosphorylation may be a potentstrategy to prevent the spreading of tau patho3logy.
Highlights
The microtubule-associated protein tau is a highly water-soluble and basic protein
To determine whether oligomeric tau from Alzheimer’s disease (AD) brain is hyperphosphorylated and/or truncated, AD O-tau was analyzed by Western blots developed with antibodies raised against specific epitopes of tau (Figure 1A and Table 1)
AD P-tau, but not PHF tau, sequesters/captures normal tau in vitro to form filaments in a non-saturable manner (Alonso et al, 1994), which was the first identification of prion-like activity of AD P-tau
Summary
The microtubule-associated protein tau is a highly water-soluble and basic protein. Normal tau stabilizes microtubules in vitro by binding to the interface between tubulin heterodimers with its microtubule-binding repeats (Kadavath et al, 2015). Tau contains more than 80 residues that can potentially be phosphorylated, and at least 18 of these sites are abnormally hyperphosphorylated in the brains of Alzheimer’s patients (Chu and Liu, 2018; Iqbal et al, 2018). Hyperphosphorylated tau detaches from microtubules, resulting in microtubule loss in neurons (Austin et al, 2017). Intrahippocampal injection of tau aggregates isolated from AD patients or produced in vitro successfully induced tau hyperphosphorylation and NFT formation at the injection sites and anatomically related regions in rodent brains, showing a similar stereotypical propagation of tau pathology as observed in AD brain
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