Abstract
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.
Highlights
Alzheimer’s disease (AD) is a late onset, progressive disease, characterized by neurodegeneration and impaired cognitive functions [1]
We first demonstrated that dynamin-related protein 1 (Drp1) interaction with fission 1 (Fis1) is induced by Aβ42, whereas no change was observed with its interaction with other adaptors in SHSY5Y cells treated with 5 μM Aβ42 for 24 hours (Figure 1A)
Since Drp1 recruitment from the cytosol to the outer mitochondrial membrane is a hallmark of activated mitochondrial fission, we determined whether blocking Drp1/Fis1 interaction by P110 treatment, is sufficient to reduce Drp1mitochondrial association
Summary
Alzheimer’s disease (AD) is a late onset, progressive disease, characterized by neurodegeneration and impaired cognitive functions [1]. Mitochondrial fragmentation (a pathological process) is caused by excessive mitochondrial fission and/or by reduced mitochondrial fusion [11, 12] Both structural and functional abnormalities of mitochondria in AD have been observed in models of AD and in patients [2,3,4, 13,14,15,16,17]. The increase in mitochondrial fission proteins and decrease in mitochondrial fusion proteins likely results in increased mitochondrial structural damage seen in brains of AD patients; this, in turn, may contribute to disease progression as damaged mitochondria produce less ATP, but they generate more damaging reactive oxygen species (ROS) that can propagate cytotoxicity of neighboring cells [1, 24]. Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and N-methyl-d-aspartate receptor antagonist (memantine) that are aimed to counteract imbalance in neurotransmission without affecting neurodegeneration per se are the only FDA-approved drugs for AD treatment, and both show only modest efficacy [31]
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