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Recently, it was shown that the γ-secretase activating protein (GSAP) regulates specifically the γ-cleavage of the β-amyloid precursor protein (APP), whose amyloidogenic processing is causatively linked to Alzheimer’s disease (AD) [1]. This paper was contradicted by many groups refuting the reproducibility of the core findings; and recently, it was shown that GSAP did not specifically affect the γ-cleavage of APP but also that the levels of the β-cleaved product of APP (sAPPβ) was reduced in cells depleted of GSAP using siRNA [2]. Here we confirm these findings that GSAP silencing also reduced Aβ and sAPPβ levels but also showed, for the first time, that rather than specifically regulating γ-secretase cleavage of APP, GSAP regulates the levels of full-length APP, thus affecting the processing of APP by all three proteases, i.e., α-, βand γ-secretases. This could explain why GSAP silencing reduces both Aβ and sAPPβ levels. Furthermore, imatinib, an anti-cancer drug that selectively reduces Aβ levels, which was shown to occur by inhibiting the GSAP-γ-secretase interaction, reduced Aβ levels also in the absence of GSAP. Thus, our results not only uncover a new aspect of GSAP function but also continue to caution the validity of GSAP as a specific therapeutic target for Aβ production in AD. Introduction GSAP was identified to be a specific regulator of γ-secretase cleavage of the amyloid precursor protein that is linked to Alzheimer’s disease. This paper published in Nature in 2010 [1]was refuted by several groups questioning the validity and reproducibility of the findings [2] [3] [4]. Recently, Udayar and Rajendran [2] showed that GSAP depletion did not only reduce Aβ but also reduced sAPPβ. Here we replicate these findings now but also show that silencing of GSAP reduced APP levels, thus explaining how GSAP could have regulated Aβ levels. These results question once again the validity of GSAP’s specific role in γ-secretase cleavage of APP but also uncovers new insights into the role of GSAP in regulating APP levels. Objective To study the role of γ-secretase activating protein (GSAP) in regulating APP processing and to study the reproducibility of GSAP’s role in specific γ-secretase cleavage of APP. γ-Secretase activating protein (GSAP) does not specifically regulate γ-cleavage of APP but regulates APP levels in

γ-Secretase Activating Protein (GSAP) does not specifically regulate γ-cleavage of APP but regulates APP levels in HeLa cells