The β-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism

摘要: Neuritic abnormalities are a major hallmark of Alzheimer's disease (AD) pathology. Accumulation β-amyloid protein (Aβ) in the brain causes changes neuritic processes individuals with this disease. In study, we show that Aβ decreases neurite outgrowth from SH-SY5Y human neuroblastoma cells. To explore molecular pathways by which alters outgrowth, examined activation and localization RhoA Rac1 regulate level phosphorylation collapsin response mediator protein-2 (CRMP-2). increased levels GTP-bound (active) form This increase GTP-RhoA correlated an alternatively spliced CRMP-2 (CRMP-2A) its threonine phosphorylated form. Both constitutively active (CA-Rac1) Rho kinase inhibitor, Y27632, decreased CRMP-2A variant caused stimulation. The amount tubulin bound to was presence but Y27632 CRMP-2. Increased both were found neurons surrounding amyloid plaques cerebral cortex APP(Swe) Tg2576 mice. We there mice decrease ability bind tubulin. results suggest Aβ-induced inhibition may be initiated through mechanism GTPase activity which, turn, phosphorylates interfere assembly neurites.