Affiliations: Department of Pharmacology, Center for Translational Medicine, Temple University, Philadelphia, PA, USA
Correspondence:
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Correspondence to: Domenico Praticò, MD, Department of Pharmacology, Temple University, 4500 North Broad Street, 947, MERB, Philadelphia, PA 19140, USA. Tel.: +1 215 707 9380; Fax: +1 215 707 9890; E-mail: praticod@temple.edu.
Abstract: Accumulation of neurotoxic amyloid-β (Aβ) is a major hallmark of Alzheimer's disease (AD) pathology and an important player in its clinical manifestations. Formation of Aβ is controlled by the availability of an enzyme called γ-secretase. Despite its blockers being attractive therapeutic tools for lowering Aβ, this approach has failed because of their serious toxic side-effects. The discovery of the γ-secretase activating protein (GSAP), a co-factor for this protease which facilitates Aβ production without affecting other pathways responsible for the toxicity, is giving us the opportunity to develop a safer anti-Aβ therapy. In this study we have characterized the effect of Imatinib, an inhibitor of GSAP, in the 3×Tg mice, a mouse model of AD with plaques and tangles. Compared with controls, mice receiving the drug had a significant reduction in brain Aβ levels and deposition, but no changes in the steady state levels of AβPP, BACE-1, ADAM-10, or the four components of the γ-secretase complex. By contrast, Imatinib-treated animals had a significant increase in CTF-β and a significant reduction in GSAP expression levels. Additionally, we observed that tau phosphorylation was reduced at specific epitopes together with its insoluble fraction. In vitro studies confirmed that Imatinib prevents Aβ formation by modulating γ-secretase activity and GSAP levels. Our findings represent the first in vivo demonstration of the biological role that GSAP plays in the development of the AD-like neuropathologies. They establish this protein as a viable target for a safer anti-Aβ therapeutic approach in AD.
Keywords: Amyloid-β, γ-secretase, imatinib, tau protein, transgenic mice
