. 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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  1. 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:

    . 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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