Blockage of GSK3 beta-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease

It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK) 3 beta-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-beta (A beta)-induced apoptosis. Therefore, blocking GSK3 beta-induced Drp1 phosphorylation may be an effective way to protect neurons from A beta toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3 beta-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce A beta-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced A beta burden and rescued the memory deficits in AD transgenic mice. Although A beta has multiple targets to exert its neurotoxicity, our findings suggested that GSK3 beta-induced mitochondrial fragmentation was, at least partially, mediated by Ab toxicity and contribute to the pathogenesis of AD. Taken together, GSK3 beta-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD. (C) 2015 Elsevier Inc. All rights reserved.