2. Academic Validation
  3. Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer's disease

Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer's disease

  • Nat Commun. 2025 Nov 26;16(1):10514. doi: 10.1038/s41467-025-65547-9.
Lu Wang # 1 2 3 4 5,  Xiao-Yong Xie # 1 2 3 4 5,  Qiu-Ling Pan 1 2 3 4 5,  Jiawei Zhang 6,  Gui-Feng Zhou 1 2 3 4 5,  Qi-Lei Zhang 7,  Xiao-Xin Yan 7,  Yu Xiang 1 2 3 4 5,  Chen-Lu Li 1 2 3 4 5,  Yi He 6,  Xiao-Jiao Xiang 8,  Xiao-Juan Deng 1 2 3 4 5,  Yan-Jiang Wang 9,  Ji-Ying Zhou 1 2 3 4 5,  Shenyou Nie 6,  Guo-Jun Chen 10 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory of Major Neurological and Mental Disorders, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Chongqing Key Laboratory of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Neurology Key Laboratory of Chongqing Education Commission of China, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 7 Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
  • 8 Department of Nuclear Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 9 Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
  • 10 Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 11 Chongqing Key Laboratory of Major Neurological and Mental Disorders, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 12 Chongqing Key Laboratory of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 13 Neurology Key Laboratory of Chongqing Education Commission of China, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 14 Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 41298370 DOI: 10.1038/s41467-025-65547-9
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.

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