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

• Published in: Molecular neurodegeneration 2017-03, Vol.12 (1), p.25-25, Article 25
• Main Authors: Guix, Francesc X, Sannerud, Ragna, Berditchevski, Fedor, Arranz, Amaia M, Horré, Katrien, Snellinx, An, Thathiah, Amantha, Saido, Takaomi, Saito, Takashi, Rajesh, Sundaresan, Overduin, Michael, Kumar-Singh, Samir, Radaelli, Enrico, Corthout, Nikky, Colombelli, Julien, Tosi, Sébastien, Munck, Sebastian, Salas, Isabel H, Annaert, Wim, De Strooper, Bart
• Format: Article
• Language: English
• Subjects: Actin; Age; AKT protein; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloidogenesis; Animals; Antibodies; Antigens; Autophagy; Biosynthesis; Blotting, Western; C-Terminus; Cell death; Computer programs; Dementia disorders; Down syndrome; Enzymes; Evolution; Exosomes - metabolism; Exosomes - ultrastructure; Hippocampus; Humans; Imaging, Three-Dimensional; Immunoglobulins; Immunohistochemistry; Lysis; Lysosomes - metabolism; Lysosomes - ultrastructure; Membrane proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Missense mutation; mRNA; Mutation; Neurodegenerative diseases; Neurons - metabolism; Peptides; Proteins; Real-Time Polymerase Chain Reaction; Rodents; Secretase; Temperature effects; Tetraspanins - metabolism; Vesicles; β-Amyloid
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-017-0165-0

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.