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

Abstract

Background: Cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-β (Aβ) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aβ₄₂ peptide while avoiding deleterious activity on Notch processing. Objective: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aβ peptides to induce neurotoxicity in rat primary cortical neurons. Methods: The effect of GSM-10h on Aβ 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 Aβ₄₂ while concomitantly increasing levels of Aβ₃₈ in the absence of effects on Aβ₄₀ levels. In TASTPM mice, GSM-10h effectively lowered brain Aβ₄₂ and increased brain Aβ₃₈, with no effect on Notch signalling. Unlike Aβ₄₂, which causes neuronal cell death, neither Aβ₃₇ nor Aβ₃₈ were neurotoxic. Conclusions: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.