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)3β-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-β 
(Aβ)-induced apoptosis. Therefore, blocking GSK3β-induced Drp1 phosphorylation 
may be an effective way to protect neurons from Aβ toxicity. To address this, we 
designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which 
could specifically block GSK3β-induced Drp1 phosphorylation. Our results 
demonstrated that TAT-Drp1-SpS treatment could significantly reduce Aβ-induced 
neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in 
hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Aβ burden and 
rescued the memory deficits in AD transgenic mice. Although Aβ has multiple 
targets to exert its neurotoxicity, our findings suggested that GSK3β-induced 
mitochondrial fragmentation was, at least partially, mediated by Aβ toxicity and 
contribute to the pathogenesis of AD. Taken together, GSK3β-induced Drp1 
phosphorylation provides a novel mechanism for mitochondrial fragmentation in 
AD, and our findings suggested a novel therapeutic strategy for AD.