Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease

Evandro F Fang; Yujun Hou; Konstantinos Palikaras; Bryan A Adriaanse; Jesse S Kerr; Beimeng Yang; Sofie Lautrup; Md Mahdi Hasan-Olive; Domenica Caponio; Xiuli Dan; Paula Rocktäschel; Deborah L Croteau; Mansour Akbari; Nigel H Greig; Tormod Fladby; Hilde Nilsen; M Zameel Cader; Mark P Mattson; Nektarios Tavernarakis; Vilhelm A Bohr

doi:10.1038/s41593-018-0332-9

Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease

Nat Neurosci. 2019 Mar;22(3):401-412. doi: 10.1038/s41593-018-0332-9. Epub 2019 Feb 11.

Authors

Evandro F Fang^#^{1

2}, Yujun Hou^#³, Konstantinos Palikaras^#^{4

5}, Bryan A Adriaanse⁶, Jesse S Kerr³, Beimeng Yang³, Sofie Lautrup³, Md Mahdi Hasan-Olive⁷, Domenica Caponio⁷, Xiuli Dan³, Paula Rocktäschel⁶, Deborah L Croteau³, Mansour Akbari⁸, Nigel H Greig⁹, Tormod Fladby^{10

11}, Hilde Nilsen⁷, M Zameel Cader⁶, Mark P Mattson^{12

13}, Nektarios Tavernarakis^{4

5}, Vilhelm A Bohr^{14

15}

Affiliations

¹ Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. e.f.fang@medisin.uio.no.
² Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway. e.f.fang@medisin.uio.no.
³ Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁴ Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
⁵ Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
⁶ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
⁷ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
⁸ Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
⁹ Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁰ Division of Medicine and Laboratory Sciences, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
¹¹ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹² Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹³ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. bohrv@grc.nia.nih.gov.
¹⁵ Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark. bohrv@grc.nia.nih.gov.

^# Contributed equally.

Abstract

Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD⁺ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ_1-42 and Aβ_1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Alzheimer Disease / psychology
Amyloid beta-Peptides / metabolism*
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Disease Models, Animal
Female
Hippocampus / metabolism*
Hippocampus / pathology*
Induced Pluripotent Stem Cells
Male
Memory
Mice
Mitophagy*
Neural Stem Cells
Neurons / metabolism*
Neurons / pathology*

Substances

Amyloid beta-Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding