|Autophagy Induction by Bexarotene Promotes Mitophagy in Presenilin 1 Familial Alzheimer's Disease iPSC-Derived Neural Stem Cells.
|Year of Publication
|Martín-Maestro P, Sproul A, Martinez H, Paquet D, Gerges M, Noggle S, Starkov AA
|2019 Jun 16
Adult neurogenesis defects have been demonstrated in the brains of Alzheimer's disease (AD) patients. The neurogenesis impairment is an early critical event in the course of familiar AD (FAD) associated with neuronal loss. It was suggested that neurologic dysfunction in AD may be caused by impaired functioning of hippocampal neural stem cells (NSCs). Multiple metabolic and structural abnormalities in neural mitochondria have long been suspected to play a critical role in AD pathophysiology. We hypothesize that the cause of such abnormalities could be defective elimination of damaged mitochondria. In the present study, we evaluated mitophagy efficacy in a cellular AD model, hiPSC-derived NSCs harboring the FAD-associated PS1 M146L mutation. We found several mitochondrial respiratory chain defects such as lower expression levels of cytochrome c oxidase (complex IV), cytochrome c reductase (complex III), succinate dehydrogenase (complex II), NADH:CoQ reductase (complex I), and also ATP synthase (complex V), most of which had been previously associated with AD. The mitochondrial network morphology and abundance in these cells was aberrant. This was associated with a marked mitophagy failure stemming from autophagy induction blockage, and deregulation of the expression of proteins involved in mitochondrial dynamics. We show that treating these cells with autophagy-stimulating drug bexarotene restored autophagy and compensated mitochondrial anomalies in PS1 M146L NSCs, by enhancing the clearance of mitochondria. Our data support the hypothesis that pharmacologically induced mitophagy enhancement is a relevant and novel therapeutic strategy for the treatment of AD.
|P01AG014930 / / National Institute on Aging /