Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's disease
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Amit U. Joshi1, Nay L. Saw2, Mehrdad Shamloo2 and Daria Mochly-Rosen1
1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
2Behavioral and Functional Neuroscience Laboratory, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Daria Mochly-Rosen, email: email@example.com
Keywords: mitochondrial dysfunction; Alzheimer’s disease; Drp1; P110; patient-derived fibroblasts
Received: October 03, 2017 Accepted: November 26, 2017 Published: December 22, 2017
Mitochondrial dynamics, involving a balance between fusion and fission, regulates mitochondrial quality and number. Increasing evidence suggests that dysfunctional mitochondria play a role in Alzheimer’s disease (AD). We observed that Drp1 interaction with one of the adaptors, Fis1, is significantly increased in Aβ-treated neurons and AD patient-derived fibroblasts. P110, a seven-amino acid peptide, which specifically inhibits Drp1/Fis1 interaction without affecting the interaction of Drp1 with its other adaptors, attenuated Aβ42-induced mitochondrial recruitment of Drp1 and prevented mitochondrial structural and functional dysfunction in cultured neurons, in cells expressing mutant amyloid precursor protein (KM670/671NL), and in five different AD patient-derived fibroblasts. Importantly, sustained P110 treatment significantly improved behavioral deficits, and reduced Aβ accumulation, energetic failure and oxidative stress in the brain of the AD mouse model, 5XFAD. This suggests that Drp1/Fis1 interaction and excessive mitochondrial fission greatly contribute to Aβ-mediated and AD-related neuropathology and cognitive decline. Therefore, inhibiting excessive Drp1/Fis1-mediated mitochondrial fission may benefit AD patients.
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