2. Academic Validation
  3. Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice

  • Protein Cell. 2023 Nov 27:pwad056. doi: 10.1093/procel/pwad056.
He-Zhou Huang 1,  Wen-Qing Ai 1,  Na Wei 2 3,  Ling-Shuang Zhu 1,  Zhi-Qiang Liu 1,  Chao-Wen Zhou 1,  Man-Fei Deng 1,  Wen-Tao Zhang 4,  Jia-Chen Zhang 1,  Chun-Qing Yang 1,  Ya-Zhuo Hu 5,  Zhi-Tao Han 5,  Hong-Hong Zhang 5,  Jian-Jun Jia 5,  Jing Wang 6,  Fang-Fang Liu 1,  Ke Li 1,  Qi Xu 7,  Mei Yuan 4,  Hengye Man 8,  Ziyuan Guo 9,  Youming Lu 1,  Kai Shu 6,  Ling-Qiang Zhu 1,  Dan Liu 10
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology; Wuhan, Hubei 430030, China.
  • 2 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, No.1 Jian She Dong Avenue, Zhengzhou, 450002, China.
  • 3 Department of Pathology, School of Basic Medicine, Zhengzhou University, No.100 Ke Xue Avenue, Zhengzhou, 450002, China.
  • 4 The Second Affiliated Hospital, Department of Neurology, Hengyang Medical School, University of South China; Hengyang, Hunan, 421001, China.
  • 5 Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Disease, Institute of Geriatrics, Chinese PLA General Hospital and Chinese PLA Medical Academy, Beijing, China.
  • 6 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 7 Department of Neurology, Union Hospital, Huazhong University of Science and Technology; Jiefang Avenue No. 1277, 430022, Wuhan, China.
  • 8 Department of Biology, Boston University; Boston, MA 02215, USA.
  • 9 Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center; Cincinnati, OH 45229, USA.
  • 10 Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology; Wuhan, Hubei 430030, China.
PMID: 38011644 DOI: 10.1093/procel/pwad056
Abstract

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of AD cases without any family history. Although genome-wide association studies (GWAS) have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 DG-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fiber boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which in turn further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence (AI)-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

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