SCR-1693 inhibits tau phosphorylation and improves insulin resistance associated cognitive deficits.

Neuropharmacology
Aijing BiLan Luo

Abstract

Except for few symptoms-improved drugs for Alzheimer's disease (AD), no disease-modified drug has been developed, especially for AD in type 2 diabetes mellitus (T2DM). SCR-1693, a disease-mortified candidate for AD, which is now in Phase I clinical study in China, improves Aβ25-35-impaired cognitive function in rodent's models. Here we report the effect of SCR-1693 on regulation of tau phosphorylation and insulin resistance associated cognition, and illustrate its underlying mechanism. We found that in intracerebroventricular injection of streptozotcin (STZ) rats, oral administration of SCR-1693 dose-dependently improved the learning and memory in Morris water maze test, decreased tau hyperphosphorylation, astrogliosis and postsynaptic protein loss in hippocampus. In Neura-2a cells with stable transfection of full-length human tau (Neura-2a-tau), treatment of SCR-1693 concentration-dependently enhanced the activation of protein phosphatase (PP1) and protein phosphatase 2A (PP2A), decreased cellular tau phosphorylation, and increased insulin-induced cellular signaling to reverse insulin resistance. Pre-treatment with the inhibitor of PP1 and PP2A inhibited the effect of SCR-1693 on both of tau phosphorylation and insulin signali...Continue Reading

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