TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β42 Lowering by GSM-10h

Background: Cleavage of the amyloid precursor protein (APP) by beta-site APP-cleaving enzyme and gamma-secretase results in the generation of amyloid-beta (A beta) peptides that aggregate and deposit as senile plagues in brains of Alzheimer disease patients. Due to the fundamental role gamma-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of gamma-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of gamma-secretase activity to selectively decrease levels of A beta(42) peptide while avoiding deleterious activity on Notch processing. Objective: Here, we describe the in vitro and in vivo characterisation of a novel gamma-secretase modulator, GSM-10h, and investigate the potential for shorter A beta peptides to induce neurotoxicity in rat primary cortical neurons. Methods: The effect of GSM-10h on A beta levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. Results: In cells, GSM-10h decreased levels of A beta(42) while concomitantly increasing levels of A beta(38) in the absence of effects on A beta(40) levels. In TASTPM mice, GSM-10h effectively lowered brain A beta(42) and increased brain A beta(38), with no effect on Notch signalling. Unlike A beta(42), which causes neuronal cell death, neither A beta(37) nor A beta(38); were neurotoxic. Conclusions: These findings confirm GSM-10h exhibits the profile of a gamma-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a gamma-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of gamma-secretase modulators. Copyright (C) 2010 5. Karger AG, Basel