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
Citations
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The emerging role of autophagy and mitophagy in tauopathies: From pathogenesis to translational implications in Alzheimer’s disease
Xiaolan Liu,Meng Ye,Liang Ma +2 more
TL;DR: Novel therapeutic strategies targeting autophagy, mitophagy and neuroinflammation, such as those using rapamycin, urolithin, spermidine, curcumin, nicotinamide, and actinonin, for the prevention and treatment of AD are highlighted.
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Molecular targets and approaches to restore autophagy and lysosomal capacity in neurodegenerative disorders.
TL;DR: In this article, the authors conceptualized mechanistic and genetic evidence pointing towards autophagy and lysosomal dysfunction as a causal driver of neurodegeneration and discussed rate-limiting pathway nodes and potential approaches to restore pathway activity.
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Mechanisms of neurodegeneration in Parkinson's disease: keep neurons in the PINK1
TL;DR: Experiments in murine primary neurons examined another possible neuroprotective function of PINK1, namely its involvement in mitochondrial motility along axons and dendrites, and underline the need for a broader characterization of its function in neurons.
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Neuronal-specific septin-3 binds Atg8/LC3B, accumulates and localizes to autophagosomes during induced autophagy
Vilmos Tóth,Henrietta Vadászi,Lilla Ravasz,Dániel Mittli,Dominik Mátyás,Tamás Molnár,András Micsonai,Tamás Szaniszló,Péter Lõrincz,Reka Kovacs,Tünde Juhász,Tamás Beke-Somfai,Gábor Juhász,Balázs A. Györffy,Katalin A. Kékesi,József Kardos +15 more
TL;DR: In this article , it was shown that septin-3 is capable of binding Atg8 homolog microtubule-associated protein 1 light chain 3B (LC3B), besides another homolog, GABA receptor associated protein-like 2 (GABARAPL2).
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The Potential Roles of Redox Enzymes in Alzheimer's Disease: Focus on Thioredoxin.
TL;DR: In this article, the role of the third redox enzyme thioredoxin (Trx), an important multifunctional protein regulating cellular redox status, has been discussed.
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