Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease
Evandro Fei Fang,Yujun Hou,Konstantinos Palikaras,Bryan A. Adriaanse,Jesse S. Kerr,Beimeng Yang,Sofie Lautrup,Mahdi Hasan-Olive,Domenica Caponio,Xiuli Dan,P Rocktäschel,Deborah L. Croteau,Mansour Akbari,Nigel H. Greig,Tormod Fladby,Hilde Nilsen,M Z Cader,Mark P. Mattson,Nektarios Tavernarakis,Nektarios Tavernarakis,Vilhelm A. Bohr,Vilhelm A. Bohr +21 more
TLDR
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 is provided, suggesting that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and thatMitophagy represents a potential therapeutic intervention.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 Aβ1-42 and Aβ1-40 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.read more
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Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing.
TL;DR: In this article, the authors provide an updated review on the biological activity, safety, and possible side effects of NAD+ precursors in preclinical and clinical studies, focusing on three major NAD+ pre-clinical and human studies.
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Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation
TL;DR: Simulation experiments aid in elucidating neurodegenerative triggers in the onset of AD for different genetic conditions, and show that oxidative stress signaling does not substantially protect cells from all the early stressors of aging, but that it is essential in preventing a late-life degenerative cellular phenotype.
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Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models
Randall Chin,Rishi Rakhit,Dara Ditsworth,Chengzhong Wang,Johan Bartholomeus,Song Liu,Akash Mody,Alex Laishu,Andrea N. Eastes,Chao Tai,Roy Y Kim,Jessica Li,S. Hansberry,Saurabh Khasnavis,Victoria A. Rafalski,Donald Herendeen,Virginia G. Garda,Jennie Phung,Daniel de Roulet,Alban Ordureau,J. Wade Harper,Shawn Johnstone,Jan Stöhr,Nicholas T. Hertz +23 more
TL;DR: In this paper , a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy, was synthesized and demonstrated that pathological α-synuclein deposition, the hallmark pathology of idiopathic Parkinson, induces mitochondrial dysfunction and impairs mitophy, driving accumulation of the pINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo.
Journal ArticleDOI
Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies
TL;DR: The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.
Posted ContentDOI
Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism
Nathan A McChesney,Jeremy L. Barth,Jeffrey Rumschlag,Junying Zeng and Zhiliang Tan,Adam J. Harrington,Kenyaria V. Noble,Carolyn M. McClaskey,P. Reginald Elvis,Silvia G. Vaena,Martin J. Romeo,Kelly C. Harris,Christopher W. Cowan,Hainan Lang +12 more
TL;DR: This is the first report of peripheral auditory nerve impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits.
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