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Mol Neurodegener. 2017 Mar 10;12(1):25. doi: 10.1186/s13024-017-0165-0.

Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments.

Author information

1
VIB Center for Brain and Disease research - VIB, Leuven, Belgium. fguixrafols@gmail.com.
2
Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium. fguixrafols@gmail.com.
3
VIB Center for Brain and Disease research - VIB, Leuven, Belgium.
4
Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium.
5
School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
6
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.
7
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, 351-0198, Saitama, Japan.
8
Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.
9
Molecular Pathology Group, Cell Biology & Histology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium.
10
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, c. Baldiri Reixac 10, 08028, Barcelona, Spain.
11
VIB Center for Brain and Disease research - VIB, Leuven, Belgium. Bart.destrooper@cme.vib-kuleuven.be.
12
Center of Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KULeuven, Leuven, Gasthuisberg O&N, Belgium. Bart.destrooper@cme.vib-kuleuven.be.
13
Dementia Research Institute (DRI-UK), University College London, Queen Square, WC1N 3BG, London, UK. Bart.destrooper@cme.vib-kuleuven.be.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Alzheimer’s disease; Amyloid precursor protein; Intraluminal vesicles; Multivesicular bodies; Tetraspanin-6

PMID:
28279219
PMCID:
PMC5345265
DOI:
10.1186/s13024-017-0165-0
[Indexed for MEDLINE]
Free PMC Article

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