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

Autor: Chenglong Xie, Xu-Xu Zhuang, Zhangming Niu, Ruixue Ai, Sofie Lautrup, Shuangjia Zheng, Yinghui Jiang, Ruiyu Han, Tanima Sen Gupta, Shuqin Cao, Maria Jose Lagartos-Donate, Cui-Zan Cai, Li-Ming Xie, Domenica Caponio, Wen-Wen Wang, Tomas Schmauck-Medina, Jianying Zhang, He-ling Wang, Guofeng Lou, Xianglu Xiao, Wenhua Zheng, Konstantinos Palikaras, Guang Yang, Kim A. Caldwell, Guy A. Caldwell, Han-Ming Shen, Hilde Nilsen, Jia-Hong Lu, Evandro F. Fang
Rok vydání: 2022
Předmět:
Zdroj: Nature Biomedical Engineering
ISSN: 2157-846X
Popis: 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.
Two potent mitophagy inducers, identified and characterized via unsupervised machine learning and a cross-species screening approach, ameliorated the pathology of Alzheimer’s disease in worms and mice.
Databáze: OpenAIRE
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