Alzheimer's phenotypes induced by overexpression of human presenilin 2 mutant proteins stimulate significant changes in key factors of glucose metabolism.

Alzheimer's disease (AD) is closely associated with significant defects in glucose metabolism. To investigate whether AD pathology induced by overexpression of human mutant presenilin 2 (PS2) protein induces changes in glucose metabolism, glucose-related factors were analyzed in the brain of 12-month-old neuron-specific enolase (NSE)/hPS2m transgenic (Tg) mice. NSE/hPS2m Tg mice used in this study showed AD-like phenotypes such as the accumulation of A beta-42, the increase of gamma-secretase activity and Tau hyperphosphorylation. A significant increase of glucose levels accompanied by a decrease of insulin levels was detected in NSE/hPS2m Tg mice, while the expression levels of insulin receptors were significantly decreased in NSE/hPS2m Tg mice compared to the non-Tg littermates without affecting the insulin-like growth factor (IGF) receptor. Moreover, the levels of AKT phosphorylation involved in the downregulation of the insulin receptor signaling pathway were reduced in the brain of NSE/hPS2m Tg mice compared with non-Tg littermate, although the levels of glycogen synthase kinase 3 (GSK-3) 13 phosphorylation were higher in the NSE/hPS2m Tg mice compared to non-Tg littermates. Furthermore, the levels of the expression of Glut-1 and -3 were significantly reduced in the NSE/hPS2m Tg mice compared to those of control mice without affecting the Glut-4 protein expression between the two groups of mice. In particular, the levels of the A beta-42 peptide in the brain of insulin-treated NSE/hPS2m Tg mice were found to be slightly lower compared with those of the A beta-42 peptide in the non-treated PS2 transgenic mice. Thus, the data presented in this study provide strong evidence that key factors of glucose metabolism are closely associated with the AD pathology induced by the hPS2m protein, and that insulin can serve as a potential therapeutic for AD patients.