Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

Autor: Xie C; Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.; Institute of Aging, Wenzhou Medical University, Wenzhou, China.; Oujiang Laboratory, Wenzhou, Zhejiang, China.; Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou, China., Zhuang XX; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China., Niu Z; Aladdin Healthcare Technologies Ltd., London, UK.; MindRank AI Ltd., Hangzhou, Zhejiang, China., Ai R; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Lautrup S; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Zheng S; School of Data and Computer Science, Sun Yat-sen University, Guangzhou, China., Jiang Y; MindRank AI Ltd., Hangzhou, Zhejiang, China., Han R; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Gupta TS; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Cao S; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Lagartos-Donate MJ; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Cai CZ; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China., Xie LM; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China., Caponio D; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Wang WW; Center of Traditional Chinese Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China., Schmauck-Medina T; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Zhang J; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Wang HL; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Lou G; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway., Xiao X; MindRank AI Ltd., Hangzhou, Zhejiang, China., Zheng W; Faculty of Health Sciences, University of Macau, Taipa, Macau, China., Palikaras K; Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Yang G; Cardiovascular Research Centre, Royal Brompton Hospital, London, UK.; National Heart and Lung Institute, Imperial College London, London, UK., Caldwell KA; Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Research on the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA., Caldwell GA; Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Research on the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA., Shen HM; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Faculty of Health Sciences, University of Macau, Macau, China., Nilsen H; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.; The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway., Lu JH; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China. jiahonglu@um.edu.mo., Fang EF; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway. e.f.fang@medisin.uio.no.; The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway. e.f.fang@medisin.uio.no.; Department of Geriatrics, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. e.f.fang@medisin.uio.no.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2022 Jan; Vol. 6 (1), pp. 76-93. Date of Electronic Publication: 2022 Jan 06.
DOI: 10.1038/s41551-021-00819-5
Abstrakt: A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.
(© 2022. The Author(s).)
Databáze: MEDLINE
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