β-amyloid induces pathology-related patterns of tau hyperphosphorylation at synaptic terminals
Journal
Journal of Neuropathology and Experimental Neurology
Date Issued
2018
Author(s)
HWAN-CHING TAI
Abstract
A synergy between β-amyloid (Ab) 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 Ab promotes the spreading of tauopathy. ? 2018 American Association of Neuropathologists, Inc. All rights reserved.
Subjects
Alzheimer disease; APP/PS1; Neurodegeneration; Proteomics; Synaptosome; Tau phosphorylation.; β-Amyloid
SDGs
Other Subjects
amyloid beta protein; amyloid precursor protein; casein kinase II; cyclin dependent kinase 5; follitropin; glycogen synthase kinase 3beta; histone deacetylase 1; huntingtin; mitogen activated protein kinase 1; mitogen activated protein kinase 3; polyubiquitin; presenilin 1; proline directed protein kinase; protein kinase C; protein MDM2; protein p53; tau protein; amyloid precursor protein; presenilin 1; tau protein; Alzheimer disease; animal experiment; animal tissue; Article; calcium signaling; controlled study; cytoskeleton; cytosol; human; human cell; human tissue; immunoblotting; mouse; nonhuman; priority journal; protein assembly; protein binding; protein degradation; protein motif; protein phosphorylation; protein processing; synaptic membrane; synaptosome; upregulation; affinity chromatography; animal; brain cortex; disease model; gene expression regulation; genetics; hippocampus; metabolism; mutation; pathology; phosphorylation; synapse; transgenic mouse; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Chromatography, Affinity; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Mice; Mice, Transgenic; Mutation; Phosphorylation; Presenilin-1; Synapses; Synaptosomes; tau Proteins
Publisher
Oxford University Press
Type
journal article