title: Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments.
abstract: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer's disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase.
  
  
  
  We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo.
  
  
  
  Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF.
  
  
  
  TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover.
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium. fguixrafols@gmail.com.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium. fguixrafols@gmail.com.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Guix
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Ragna
authors.initials: R
authors.lastname: Sannerud
authors.affiliation: School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Fedor
authors.initials: F
authors.lastname: Berditchevski
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Amaia M
authors.initials: AM
authors.lastname: Arranz
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Horré
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.affiliation: Department of Neurobiology, University of Pittsburgh Brain Institute, Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh School of Medicine, Biomedical Science Tower 3, Room 6062, 3501 Fifth Avenue, Pittsburgh, PA, 15213-3301, USA.
authors.forename: Amantha
authors.initials: A
authors.lastname: Thathiah
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, 351-0198, Saitama, Japan.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Saido
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, 351-0198, Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Sundaresan
authors.initials: S
authors.lastname: Rajesh
authors.affiliation: Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Overduin
authors.affiliation: Molecular Pathology Group, Cell Biology & Histology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium.
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Nikky
authors.initials: N
authors.lastname: Corthout
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, c. Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Julien
authors.initials: J
authors.lastname: Colombelli
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, c. Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tosi
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Isabel H
authors.initials: IH
authors.lastname: Salas
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Annaert
authors.affiliation: VIB Center for Brain and Disease research - VIB, Leuven, Belgium. Bart.destrooper@cme.vib-kuleuven.be.|Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium. Bart.destrooper@cme.vib-kuleuven.be.|Dementia Research Institute (DRI-UK), University College London, Queen Square, WC1N 3BG, London, UK. Bart.destrooper@cme.vib-kuleuven.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D055354:Exosomes / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D021621:Imaging, Three-Dimensional; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D059470:Tetraspanins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C115729:TSPAN6 protein, human; D059470:Tetraspanins
keywords: Alzheimer’s disease; Amyloid precursor protein; Intraluminal vesicles; Multivesicular bodies; Tetraspanin-6