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Nature Aging, 08 January 2025 | https://doi.org/10.1038/s43587-024-00790-1 EBP1 potentiates amyloid β pathology by regulating γ-secretase

Byeong-Seong Kim ^1,2,14, Inwoo Hwang ^1,2,14, 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 Lee¹¹, Daesik Kim ¹², Sung-Woo Cho ¹³ & Jee-Yin Ahn ^1,2,*

¹Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
²Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
³Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

⁴Center for Brain Disorders, Brain Science Institute Korea Institute of Science and Technology (KIST), Seoul, Korea.
⁵Department of Life Sciences, Korea University, Seoul, Korea.

⁶Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul,
Korea.
⁷Faculty of Life and Health Sciences, and Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁸Department of Biophysics, Sungkyunkwan University, Suwon, Korea.
⁹Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon, Korea.
¹⁰School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
¹¹Research Animal Resources Center, Korea Institute of Science and Technology (KIST), Seoul, Korea.
¹²Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Korea.
¹³Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul, Korea.
¹⁴These authors contributed equally: Byeong-Seong Kim, Inwoo Hwang.

^*Corresponding author: correspondence to Jee-Yin Ahn

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.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-01-09)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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