2. Academic Validation
  3. EBP1 potentiates amyloid β pathology by regulating γ-secretase

EBP1 potentiates amyloid β pathology by regulating γ-secretase

  • Nat Aging. 2025 Jan 8. doi: 10.1038/s43587-024-00790-1.
Byeong-Seong Kim # 1 2,  Inwoo Hwang # 1 2,  Hyo Rim Ko 1 2,  Young Kwan Kim 1 2,  Hee Jin Kim 3,  Sang Won Seo 3,  Yujung Choi 4 5,  Sungsu Lim 4 6,  Yun Kyung Kim 4 6,  Shuke Nie 7,  Keqiang Ye 7,  Jong-Chan Park 8,  Yunjong Lee 9,  Dong-Gyu Jo 10,  Seung Eun Lee 11,  Daesik Kim 12,  Sung-Woo Cho 13,  Jee-Yin Ahn 14 15
Affiliations

Affiliations

  • 1 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
  • 2 Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
  • 3 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 4 Center for Brain Disorders, Brain Science Institute Korea Institute of Science and Technology (KIST), Seoul, Korea.
  • 5 Department of Life Sciences, Korea University, Seoul, Korea.
  • 6 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, Korea.
  • 7 Faculty of Life and Health Sciences, and Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 8 Department of Biophysics, Sungkyunkwan University, Suwon, Korea.
  • 9 Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon, Korea.
  • 10 School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
  • 11 Research Animal Resources Center, Korea Institute of Science and Technology (KIST), Seoul, Korea.
  • 12 Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Korea.
  • 13 Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul, Korea.
  • 14 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea. jeeahn@skku.edu.
  • 15 Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea. jeeahn@skku.edu.
  • # Contributed equally.
PMID: 39779912 DOI: 10.1038/s43587-024-00790-1
Abstract

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in Aβ deposition, amyloid plaques and cognitive dysfunction. In postmortem brains of patients with AD and 5x-FAD mice, we found that EBP1 is proteolytically cleaved by asparagine endopeptidase at N84 and N204 residues, compromising its inhibitory effect on γ-secretase, increasing Aβ aggregation and neurodegeneration. Accordingly, injection of AAV2-Ebp1 wild-type or an asparagine endopeptidase-uncleavable mutant into the brains of 5x-FAD mice decreased Aβ generation and alleviated the behavioral impairments. Thus, our study suggests that EBP1 acts as an inhibitor of γ-secretase on amyloid precursor protein cleavage and preservation of functional EBP1 could be a therapeutic strategy for AD.

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