Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease

Lu Wang, Xiao-Yong Xie, Qiu-Ling Pan, Jiawei Zhang, Gui-Feng Zhou, Qi-Lei Zhang, Xiao-Xin Yan, Yu Xiang, Chen-Lu Li, Yi He, Xiao-Jiao Xiang, Xiao-Juan Deng, Yan-Jiang Wang, Ji-Ying Zhou, Shenyou Nie and Guo-Jun Chen ()
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Lu Wang: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Xiao-Yong Xie: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Qiu-Ling Pan: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Jiawei Zhang: Chongqing Medical University, Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), College of Pharmacy
Gui-Feng Zhou: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Qi-Lei Zhang: Central South University, Department of Anatomy and Neurobiology, Xiangya School of Medicine
Xiao-Xin Yan: Central South University, Department of Anatomy and Neurobiology, Xiangya School of Medicine
Yu Xiang: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Chen-Lu Li: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Yi He: Chongqing Medical University, Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), College of Pharmacy
Xiao-Jiao Xiang: The Second Affiliated Hospital of Chongqing Medical University, Department of Nuclear Medicine
Xiao-Juan Deng: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Yan-Jiang Wang: Third Military Medical University, Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital
Ji-Ying Zhou: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology
Shenyou Nie: Chongqing Medical University, Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), College of Pharmacy
Guo-Jun Chen: the First Affiliated Hospital of Chongqing Medical University, Department of Neurology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer’s disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD.

Date: 2025
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DOI: 10.1038/s41467-025-65547-9

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