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Glycogen synthase kinase-3 regulates production of amyloid-β peptides and tau phosphorylation in diabetic rat brain.

ABSTRACT: The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer's disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-β peptides (A β) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And A β 40 and A β 42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of A β overproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of A β and the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

SUBMITTER: Qu ZS

PROVIDER: S-EPMC3997149 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression.

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Project description:The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (A?) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase A? generation. Caffeine has been shown to have protective actions against AD and based on our recent findings that caffeine can inhibit endocytosis in neurons and can prevent neuronal A? generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced A? generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (A?PP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of A? as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of A?, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of A?. Caffeine also blocked HIV-1 Tat-induced increases in cellular levels of phosphorylated tau. Furthermore, caffeine blocked HIV-1 Tat-induced endolysosome dysfunction as indicated by decreased protein levels of vacuolar-ATPase and increased protein levels of cathepsin D. These results further implicate endolysosome dysfunction in the pathogenesis of AD and HAND, and by virtue of its ability to prevent and/or block neuropathological features associated with AD and HAND caffeine might find use as an effective adjunctive therapeutic agent.

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Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly.

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