Pharmacological Modulation of GSAP Reduces Amyloid-β Levels and Tau Phosphorylation in a Mouse Model of Alzheimer's Disease with Plaques and Tangles

Accumulation of neurotoxic amyloid-beta (A beta) is a major hallmark of Alzheimer's disease (AD) pathology and an important player in its clinical manifestations. Formation of A beta is controlled by the availability of an enzyme called gamma-secretase. Despite its blockers being attractive therapeutic tools for lowering A beta, this approach has failed because of their serious toxic side-effects. The discovery of the gamma-secretase activating protein (GSAP), a co-factor for this protease which facilitates A beta production without affecting other pathways responsible for the toxicity, is giving us the opportunity to develop a safer anti-A beta therapy. In this study we have characterized the effect of Imatinib, an inhibitor of GSAP, in the 3xTg mice, a mouse model of AD with plaques and tangles. Compared with controls, mice receiving the drug had a significant reduction in brain A beta levels and deposition, but no changes in the steady state levels of A beta PP, BACE-1, ADAM-10, or the four components of the gamma-secretase complex. By contrast, Imatinib-treated animals had a significant increase in CTF-beta 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 A beta formation by modulating gamma-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-A beta therapeutic approach in AD.