Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain

Abstract

Brain protein kinase B (Akt) and glycogen synthase kinase-3 (GSK-3) activities are adaptable to changes of peripheral blood glucose level in vivo. GSK-3 phosphorylates microtube-associated protein tau at multiple sites, which can be antagonized by protein phosphatase-2A (PP-2A). The imbalance among these enzymes might have potential connections with diabetes mellitus (DM) and Alzheimer's disease (AD). In this study hyperglycemia rat DM model was achieved by streptozotocin (STZ) treatment. The phosphorylation of tau in the rat hippocampus was detected with specific antibodies. Insulin and Li2CO3 administration were also employed to find out the regulatory efforts of the kinases. We observed that rat hippocampus tau was hyperphosphorylated at Ser396/Ser404 (PHF-1 sites) in STZ-induced DM model, accompanied by lowered phosphorylation levels of Akt, GSK-3 and PP-2A. Lithium, a specific GSK-3 inhibitor, nearly reversed all phosphorylation of tau at above sites in 30days. Insulin administration restored the blood glucose level in DM rats but suppressed PP-2A activity, resulting in the PHF-1 sites of tau not being dephosphorylated. These findings strongly suggest that STZ-induced hyperglycemia may cause disorder of Akt/GSK-3/PP-2A regulations in rat brain and further lead to abnormal phosphorylation of hippocampus tau.