@article{2980572,
    title = "Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow",
    author = "Xie, C. and Zhuang, X.-X. and Niu, Z. and Ai, R. and Lautrup, S. and Zheng, S. and Jiang, Y. and Han, R. and Gupta, T.S. and Cao, S. and Lagartos-Donate, M.J. and Cai, C.-Z. and Xie, L.-M. and Caponio, D. and Wang, W.-W. and Schmauck-Medina, T. and Zhang, J. and Wang, H.-L. and Lou, G. and Xiao, X. and Zheng, W. and Palikaras, K. and Yang, G. and Caldwell, K.A. and Caldwell, G.A. and Shen, H.-M. and Nilsen, H. and Lu, J.-H. and Fang, E.F.",
    journal = "Nature Biomedical Engineering",
    year = "2022",
    volume = "6",
    number = "1",
    pages = "76-93",
    publisher = "Institute of Geographic Sciences and Natural Resources Research",
    issn = "2157-846X",
    doi = "10.1038/s41551-021-00819-5",
    keywords = "Diagnosis;  Flavonoids;  Machine learning;  Neurodegenerative diseases;  Neurons, Age-related;  Alzheimer;  Cross-species;  Experimental validations;  Mitochondrias;  Neurodegenerative;  Pharmacophores;  Unsupervised machine learning;  Vector representations;  Work-flows, Pathology",
    abstract = "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)."
}