P3–304: Mnb/Dyrk1A primes phosphorylation of tau at several phosphorylation sites by GSK–3β

Background: In Alzheimer’s disease brains (AD), amyloid A is abnormally deposited in senile plaques (SPs) and hyperphosphorylated tau in neurons bearing neurofibrillary tangles (NFTs). In vivo evidence has demonstrated that A can induce tau hyperphosphorylation and tangle formation, but the underlying mechanism remains largely elusive. Objective(s): Whether or not in AD brains A plays a causal role in the reduced PP2A activity towards to tau, and PP2A bridges A and PHF-tau pathologies are of imperative to clarify. Methods: Our results showed that in the homogenates of the medial temporal cortex, levels of phosphorylated (p) PP2A catalytic subunit (PP2AC) (Y307) / total PP2AC ( 2-fold) and demethylated (-m) PP2AC (L309) /total PP2AC ( 1.5-fold), PHF-1, A 42, and A 43 were significantly increased in AD relative to control. p-PP2AC (Y307) co-existed with NFTs (AT8) that encircled SPs labeled by 4G8. In both mouse APPswe N2a and transgenic APPswe /PS1 (A246E) mice that have overexpress A , levels of p-PP2AC (Y307), p-GSK-3 (S9 and/or Y216), p-P70S6K (T421/S424 and T389) and p-tau (S205, PHF-1, AT180) were dramatically increased, but levels of methylated ( m) PP2AC (L309) and de-p-tau at Tau-1 sites were significantly decreased relative to controls. A similar pattern of responses of p-PP2AC (Y307) and -m-PP2AC (L309), p-GSK-3 (S9 and/or Y216), p-P70S6K (T421/S424 and T389), tau (S205, Tau-1, PHF-1, and T180) was seen in wild-type N2a cells and APPswe N2a cells treated with okadaic acid. Conclusions: Together, it suggested that up-regulated p-PP2AC (Y307) and down-regulated m-PP2AC contribute to the reduced PP2A activity in AD brains, resulting in activation of GSK-3 and p70S6K and the compromised dephosphorylation of abnormally hyperphosphorylated tau. The deregulation of PP2AC might play a critical role in A -mediated tau hyperphosphorylation in AD.