2. Academic Validation
  3. RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease

RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease

  • Acta Neuropathol Commun. 2025 Sep 24;13(1):198. doi: 10.1186/s40478-025-02115-8.
Miao-Jin Ji # 1,  Yun Li # 1 2,  Jiao Yang # 1 3,  Kangjunjie Wang 4 5,  Shuning Sang 1,  Hong Yang 1,  Chenhao Tian 1,  Xin Tang 1 6,  Ji-Heng Cai 1 7,  Tianhan He 1,  Cheng Zhang 1,  Huanyao Tang 1,  Tiantao Cui 1,  Xinran Meng 1,  Xiang Cao 1,  Jiaqi Zhu 8,  Jie Wang 8,  Jun-Li Cao 9,  Daming Gao 10,  Chao Liu 11
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China.
  • 2 Department of Anesthesiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
  • 3 Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
  • 5 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 6 Department of Anesthesiology, Jianhu People's Hospital of Jiangsu Province, Yancheng, China.
  • 7 Department of Anesthesiology, Sheyang County People's Hospital, Yancheng, China.
  • 8 The First School of Clinical Medicine, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China.
  • 9 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China. caojl0310@aliyun.com.
  • 10 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. dgao@sibcb.ac.cn.
  • 11 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China. Chaoliu@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 40993809 DOI: 10.1186/s40478-025-02115-8
Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly, with limited effective treatments available in clinical practice. Impaired glucose metabolism has long been observed in the brains of AD patients, yet the mechanisms linking metabolic signals to AD pathogenesis remain elusive. Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation. Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD. Genetic dephosphorylation of RNF168 S60 enhances DNA damage response, reduces double-strand breaks (DSBs), and ameliorates learning and memory deficits in Aβ-based mouse models of AD. Mechanistically, RNF168 S60 phosphorylation impairs long-term potentiation (LTP) of mossy fiber-CA3 synapses in the hippocampus. Importantly, genetic dephosphorylation of RNF168 S60 rescues the deficits in Mossy fiber-CA3 synapse LTP, AD-related spine loss and Aβ pathology. Pharmacological inhibition of RNF168 phosphorylation by S6K1 inhibitor PF-4,708,671 alleviated learning and memory deficits. Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation. Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer's disease.

Keywords

Alzheimer’s disease; DNA double-strand breaks; Learning and memory; Phosphorylation; RNF168; Synaptic plasticity.

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