S4-03-02

The cytoplasmic isoform of ribosomal S6 kinase 1 (RSK1), the 70–kDa S6 kinase (p70S6K), is a Ser/Thr (S/T) –directed kinase that regulates the phosphorylation of the 40S ribosomal protein S6. Phosphorylation and activation of p70S6K have been suggested to be mediated by both phosphoinositol 3–kinase (PI3K) and mitogen–activated protein kinase (MAPK) pathways. Our previous studies indicated that both PI3K and MAPK pathways are aberrantly regulated in Alzheimer's disease (AD) brains. In the study, we wanted to investigate the role of p70S6K in AD pathogenesis. In a series of studies, we found: 1) an increased immunoreactivity of the phosphorylated (p) / activated form of p70S6K, and its upstream kinase: mammalian target of rapamycin, in AD as compared with control brains; 2) a colocalization of p–p70S6K with PHF–tau in neurons bearing neurofibrillary tangles (NFTs) and pre–tangles; 3) that p70S6K activation and tau hyperphosphorylation can be induced by a selective protein phosphatase (PP) –2A inhibition in rat brain slices, as well as 100 μM zinc in SH–SY5Y cells and primary cultured neurons; 4) that phosphorylation and activation of p70S6K are preferentially regulated by the PI3K pathway, together with the MAPK pathway; 5) that p70S6K can mediate tau phosphorylation and synthesis; and 6) that p70S6K activation does not increase phosphorylation of neurofilament. These suggested p70S6K might play a significant role in tau abnormalities such as hyperphosphorylation, accumulation, assembly into paired helical filaments and neurofibrillary tangle formation, accompanied by microtubule disruption. Activation of p70S6K in AD might be caused by either upregulated PI3K and MAPK pathways, or downregulated PP–2A.