Amyloid-β Modulates Both AβPP and Tau Phosphorylation

Two histopathological hallmarks of Alzheimer's disease (AD), the tau rich neurofibrillary tangles and the senile plaques, predominating in amyloid-beta (A beta), have fueled research in distinct directions. Evidence suggests that A beta triggers imbalanced activities of protein phosphatases and kinases thus affecting the phosphorylation state of tau in AD. The amyloid-beta protein precursor (A beta PP) itself appears to be hyperphosphorylated at different residues in AD brains, including at Thr668. The results reported in this manuscript show, for the first time, that A beta(42) can impact upon the A beta PP phosphorylation state at the Thr668 residue. This novel finding supports a putative model, whereby A beta can modulate the phosphorylation state of A beta PP regulating its processing and consequently its own production. Furthermore, the data presented shows that in primary cortical neurons, GSK3 beta and Cdk5 are involved in A beta PP phosphorylation at this residue and that PP1 and PP2B participate in A beta PP dephosphorylation. Consistent with other reports, A beta was capable of increasing tau phosphorylation at the Ser396 and Ser262 residues. This peptide is therefore a strong candidate for promoting the cross talk between signaling pathways, which simultaneously result in A beta PP and tau hyperphosphorylation. In closing, the A beta effect on protein kinases and protein phosphatases may constitute an alternative mechanism by which the peptide is able to modulate the phosphorylation state of both A beta PP and tau in AD.