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Autophagy Induction by Bexarotene Promotes Mitophagy in Presenilin 1 Familial Alzheimer’s Disease iPSC-Derived Neural Stem Cells

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Abstract

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.

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Abbreviations

(AD):

Alzheimer’s disease

(Aβ):

amyloid beta

(APP):

amyloid beta (A4) precursor protein

(AVs):

autophagic vacuoles

(Baf A1):

bafilomycin A1

(CCCP):

carbonyl cyanide m-chlorophenylhydrazone

(DLP1):

dynamin-like protein 1

(FAD):

familial Alzheimer’s disease

(GAPDH):

glyceraldehyde-3-phosphate dehydrogenase

(iPSC):

induced pluripotent stem cells

HAR:

hexaammineruthenium (III)

(LAMP1):

lysosomal-associated membrane protein 1

(MAP1LC3/LC3):

microtubule-associated protein 1 light chain 3

(mtDNA):

mitochondrial DNA

(MFN1):

mitofusin 1

(MFN2):

mitofusin 2

(NPCs):

neural progenitor cells

(OPA1):

optic atrophy 1

(OPTN):

optineurin

(OXPHOS):

oxidative phosphorylation system

(PSEN):

presenilin

(PINK1):

PTEN-induced putative kinase 1

(ROS):

reactive oxygen species

(RXR):

retinoid X receptor

(TFEB):

transcription factor EB

(TOMM20):

translocase of outer mitochondrial membrane 20 homolog

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Acknowledgments

We would like to thank Marc Tessier-Lavigne for supporting the generation of cell lines, Matt Zimmer for performing FACS on GFP/RFP double-transfected cells to help generate PS1 M146L knockin iPSCs, Brian Campos for technical assistance in screening candidate clones, and Ana Sevilla for performing iPSC immunostaining characterization.

Funding

This work was supported by the NIA Grant P01AG014930 (A.A.S. and S.N.).

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Authors and Affiliations

  1. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA

    Patricia Martín-Maestro, Meri Gerges & Anatoly A. Starkov

  2. Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

    Andrew Sproul

  3. The New York Stem Cell Foundation, New York, NY, USA

    Hector Martinez & Scott Noggle

  4. Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany

    Dominik Paquet

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  1. Patricia Martín-Maestro
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  2. Andrew Sproul
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  6. Scott Noggle
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Contributions

PMM designed, performed, analyzed, and interpreted data as well as wrote the manuscript; AS, HM, DP, MTL CLM, and SN generated hiPSC-derived NSCs harboring the FAD-associated mutation. MG performed OXPHOS studies. AS and AAS contributed to data interpretation and manuscript editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Patricia Martín-Maestro.

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Human subject research at the New York Stem Cell Foundation was performed in accordance with applicable federal and state regulations, as well as with guidelines established by the National Institutes of Health (NIH), National Academy of Sciences (NAS), and International Society for Stem Cell Research (ISSCR). It was also fully compliant with standards outlined in the Health Insurance Portability and Accountability Act (HIPAA) and in the Office for Human Research Protections (OHRP) recommendations.

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Martín-Maestro, P., Sproul, A., Martinez, H. et al. Autophagy Induction by Bexarotene Promotes Mitophagy in Presenilin 1 Familial Alzheimer’s Disease iPSC-Derived Neural Stem Cells. Mol Neurobiol 56, 8220–8236 (2019). https://doi.org/10.1007/s12035-019-01665-y

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  • DOI: https://doi.org/10.1007/s12035-019-01665-y

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