| First Author | Yan J | Year | 2015 |
| Journal | Neurobiol Aging | Volume | 36 |
| Issue | 1 | Pages | 211-27 |
| PubMed ID | 25192600 | Mgi Jnum | J:218439 |
| Mgi Id | MGI:5617463 | Doi | 10.1016/j.neurobiolaging.2014.08.005 |
| Citation | Yan J, et al. (2015) Blockage of GSK3beta-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease. Neurobiol Aging 36(1):211-27 |
| abstractText | 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)3beta-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 (Abeta)-induced apoptosis. Therefore, blocking GSK3beta-induced Drp1 phosphorylation may be an effective way to protect neurons from Abeta toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3beta-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce Abeta-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Abeta burden and rescued the memory deficits in AD transgenic mice. Although Abeta has multiple targets to exert its neurotoxicity, our findings suggested that GSK3beta-induced mitochondrial fragmentation was, at least partially, mediated by Abeta toxicity and contribute to the pathogenesis of AD. Taken together, GSK3beta-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD. |
