β-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals

Hsin-Yi Wu, Po-Cheng Kuo, Yi-Ting Wang, Hao-Tai Lin, Allyson D Roe, Bo Y Wang, Chia-Li Han, Bradley T Hyman, Yu-Ju Chen, Hwan-Ching Tai

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Abstract

A synergy between β-amyloid (Aβ) and tau appears to occur in Alzheimer disease (AD), but the mechanisms of interaction, and potential locations, are little understood. This study investigates the possibility of such interactions within the cortical synaptic compartments of APP/PS1 mice. We used label-free quantitative mass spectrometry to study the phosphoproteome of synaptosomes, covering 2400 phosphopeptides and providing an unbiased survey of phosphorylation changes associated with amyloid pathology. Hyperphosphorylation was detected on 36 synaptic proteins, many of which are associated with the cytoskeleton. Importantly, tau is one of the most hyperphosphorylated proteins at the synapse, upregulated at both proline-directed kinase (PDK) sites (S199/S202, S396/S404) and nonPDK sites (S400). These PDK sites correspond to well-known pathological tau epitopes in AD patients, recognized by AT8 and PHF-1 antibodies, respectively. Hyperphosphorylation at S199/S202, a rarely examined combination, was further validated in patient-derived human synaptosomes by immunoblotting. Global surveys of upregulated phosphosites revealed 2 potential kinase motifs, which resemble those of cyclin-dependent kinase 5 (CDK5, a PDK) and casein kinase II (CK2, a nonPDK). Our data demonstrate that, within synaptic compartments, amyloid pathology is associated with tau hyperphosphorylation at disease-relevant epitopes. This provides a plausible mechanism by which Aβ promotes the spreading of tauopathy.

Original languageEnglish
Pages (from-to)814-826
Number of pages13
JournalJournal of Neuropathology and Experimental Neurology
Volume77
Issue number9
DOIs
Publication statusPublished - Sep 1 2018

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Wu, H-Y., Kuo, P-C., Wang, Y-T., Lin, H-T., Roe, A. D., Wang, B. Y., Han, C-L., Hyman, B. T., Chen, Y-J., & Tai, H-C. (2018). β-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals. Journal of Neuropathology and Experimental Neurology, 77(9), 814-826. https://doi.org/10.1093/jnen/nly059