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J Neuropathol Exp Neurol ; 77(9): 814-826, 2018 09 01.
Article in English | MEDLINE | ID: mdl-30016458

ABSTRACT

A synergy between ß-amyloid (Aß) 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 Aß promotes the spreading of tauopathy.


Subject(s)
Alzheimer Disease/pathology , Cerebral Cortex/pathology , Hippocampus/pathology , Synapses/metabolism , Synaptosomes/pathology , tau Proteins/metabolism , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Chromatography, Affinity , Disease Models, Animal , Gene Expression Regulation/genetics , Humans , Mice , Mice, Transgenic , Mutation/genetics , Phosphorylation , Presenilin-1/genetics , Synapses/pathology , Synaptosomes/metabolism
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