title: Sorting nexin-4 regulates β-amyloid production by modulating β-site-activating cleavage enzyme-1.
abstract: BACKGROUND
  Amyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer's disease (AD). Aβ generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. Although sorting nexin (SNX) family proteins regulate this trafficking, the relevance and role of sorting nexin-4 (SNX4) regarding AD has not been studied yet.
  
  
  METHODS
  In this study, human brain tissue and APP/PS1 mouse brain tissue were used to check the disease relevance of SNX4. To investigate the role of SNX4 in AD pathogenesis, several experiments were done, such as coimmunoprecipitation, Western blotting, immunohistochemistry, and gradient fractionation.
  
  
  RESULTS
  We found that SNX4 protein levels changed in the brains of patients with AD and of AD model mice. Overexpression of SNX4 significantly increased the levels of BACE1 and Aβ. Downregulation of SNX4 had the opposite effect. SNX4 interacts with BACE1 and prevents BACE1 trafficking to the lysosomal degradation system, resulting in an increased half-life of BACE1 and increased production of Aβ.
  
  
  CONCLUSIONS
  We show that SNX4 regulates BACE1 trafficking. Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1-mediated β-processing of APP and subsequent Aβ generation.
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul, 05505, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul, 05505, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Mi-Hyang
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul, 05505, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Won
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul, 05505, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hoe-Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. ysy@amc.seoul.kr.|Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul, 05505, Korea. ysy@amc.seoul.kr.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea. ysy@amc.seoul.kr.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea. ysy@amc.seoul.kr.
authors.forename: Seung-Yong
authors.identifier: http://orcid.org/0000-0002-0133-2934
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. dhkim@amc.seoul.kr.|Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul, 05505, Korea. dhkim@amc.seoul.kr.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea. dhkim@amc.seoul.kr.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea. dhkim@amc.seoul.kr.
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D058305:Sorting Nexins / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; C513981:SNX4 protein, human; C000623392:SNX4 protein, mouse; D058305:Sorting Nexins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse
keywords: APP; Alzheimer’s disease; BACE1; Lysosome; Sorting nexin