Abstract
Diabetes mellitus (DM) increases the risk for cognitive impairment and Alzheimer's disease (AD). Diabetic ketoacidosis (DKA), a serious complication of DM, may also cause brain damage and further AD, but the underlying molecular mechanisms remain unclear. Our objective was to understand how DKA can promote neurodegeneration in AD. We induced DKA in rats through intraperitoneal injection of streptozotocin, followed by starvation for 48 hours and investigated AD-related brain alterations focusing on tau phosphorylation. We found that DKA induced hyperphosphorylation of tau protein at multiple sites associated with AD. Studies of tau kinases and phosphatases suggest that the DKA-induced hyperphosphorylation of tau was mainly mediated through activation of c-Jun N-terminal kinase and downregulation of protein phosphatase 2A. Disruption of the mTOR-AKT (the mechanistic target of rapamycin-protein kinase B) signaling pathway and increased levels of synaptic proteins were also observed in the brains of rats with DKA. These results shed some light on the mechanisms by which DKA may increase the risk for AD.
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