Guix FX, Sannerud R, Berditchevski F, Arranz AM, Horré K, Snellinx A, Thathiah A, Saido T, Saito T, Rajesh S, Overduin M, Kumar-Singh S, Radaelli E, Corthout N, Colombelli J, Tosi S, Munck S, Salas IH, Annaert W, De Strooper B. Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments. Mol Neurodegener. 2017 Mar 10;12(1):25. PubMed.
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Translational Neuroscience Laboratory, Campus Biotech Innovation Park & Fondation Eclosion
In this study, Guix and colleagues report that the protein tetraspanin 6 (TSPAN6) plays a critical role in lysosomal APP-C-terminal fragment (CTF) turnover. First, the authors show that overexpression of TSPAN6 in HEK-APP cells increased both APP-CTFs and Aβ levels, while siRNA depletion of TSPAN6 in the same cells reduced both APP-CTFs and Aβ levels (Fig. 1). These findings are consistent with previous work showing that TSPAN6 positively regulates the processing of APP-CTFs and the production of Aβ peptides (Mosser et al., 2015). In the latter, Mosser and colleagues identified TSPAN6 in the interactome of active γ-secretase, and found that siRNA-reduced expression of TSPAN6 in HEK-APPSwe or HeLa cells drastically lowered both APP-CTFs and Aβ levels (Figs. 1b-d). Importantly, Guix and colleagues confirmed these effects in vivo, both in Tspan6 knockout (KO) and Tspan6 KO/App mice, and further show that TSPAN6 affects autophagosome-lysosomal fusion, slowing down the degradation of APP-CTFs. Interestingly, Mosser and colleagues also demonstrated that the protein APMAP (identified as part of the γ-secretase interactome) negatively regulates Aβ production by modulating the transport of APP-CTFs to the lysosomal/autophagic system, and consequently their degradation (Mosser et al., 2015).
Altogether, these findings further support the endosomal trafficking and lysosomal/authophagic degradation of APP-CTFs as important regulators of Aβ production in the brain. Understanding how these functions evolve during aging is definitively important to better understand the patho-biological events causing AD—and potentially for the development of new therapeutic strategies to slow down the progression of this disorder.
References:
Mosser S, Alattia JR, Dimitrov M, Matz A, Pascual J, Schneider BL, Fraering PC. The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain. Hum Mol Genet. 2015 Jan 15;24(2):371-82. Epub 2014 Sep 1 PubMed.
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