Quantitative phospho-proteomic analysis of pathological changes at neuronal synapses in a mouse model of Alzheimer disease

The key pathological features of Alzheimer’s disease (AD) are aggregates of Aβ peptide (plaques) and tau protein (tangles). The relation between Aβ pathology and tau pathology is a critical but unresolved issue. We previously observed that neuronal synapses in AD-affected brains showed deposits of hyperphosphorylated and misfolded tau protein. Here we investigated the cause of tau hyperphosphorylation in synapses using APP/PS1 mice and quantitative phosphoproteomics. We found 12 tau phosphosites in mouse synaptosomes, which were identical for APP/PS1 and control mice. Importantly, 6 of these sites (S199, S202, S396, S400, S404, S416) showed statistically significant increase in APP/PS1 mice. The pattern of tau hyperphosphorylation suggested the activation of proline-directed kinases (PDK) by Aβ at synapses. Through global phosphoproteomic analysis, we found 40 synaptic proteins including tau which were hyperphosphorylated, especially by proline-directed kinases and acid-directed kinases. Further motif analysis suggested cyclin-dependent kinase 5 (CDK5) as the highly activated proline-directed kinase, and casein kinase II (CK2) as the highly activated acid-directed kinase. Our data suggests that CDK5 is an important link between Aβ and tau pathology, and that blocking the activation of CDK5 may be a potential therapeutic strategy for AD.