Research and Publications - Department of Chemical & Biological Engineering
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Browsing Research and Publications - Department of Chemical & Biological Engineering by Subject "A-BETA"
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Item Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow(Nature Portfolio, 2022) Xie, Chenglong; Zhuang, Xu-Xu; Niu, Zhangming; Ai, Ruixue; Lautrup, Sofie; Zheng, Shuangjia; Jiang, Yinghui; Han, Ruiyu; Sen Gupta, Tanima; Cao, Shuqin; Lagartos-Donate, Maria Jose; Cai, Cui-Zan; Xie, Li-Ming; Caponio, Domenica; Wang, Wen-Wen; Schmauck-Medina, Tomas; Zhang, Jianying; Wang, He-ling; Lou, Guofeng; Xiao, Xianglu; Zheng, Wenhua; Palikaras, Konstantinos; Yang, Guang; Caldwell, Kim A.; Caldwell, Guy A.; Shen, Han-Ming; Nilsen, Hilde; Lu, Jia-Hong; Fang, Evandro F.; Wenzhou Medical University; University of Oslo; Oujiang Laboratory; University of Macau; Sun Yat Sen University; Athens Medical School; National & Kapodistrian University of Athens; Royal Brompton Hospital; Imperial College London; University of Alabama Tuscaloosa; University of Alabama Birmingham; National University of Singapore; Zhengzhou UniversityA 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-beta 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.