Pharmacological properties of a novel and potent γ-secretase modulator as a therapeutic option for the treatment of Alzheimer’s disease

Abstract

Previous studies of γ-secretase inhibitors (GSIs) and Notch-sparing GSIs have shown reduced amyloid-β (Aβ) peptide levels but increased Notch-related and -unrelated adverse effects. In this study, we examined the effects of compound-1 on Aβ processing and cognitive function and assessed Notch-related and -unrelated adverse effects. Compound-1 reduced Aβ40 and Aβ42 levels but inversely increased Aβ37 in Neuro2a cells, leading to no net changes in total Aβ levels, indicating that compound-1 is a γ-secretase modulator (GSM). In time-course experiments, compound-1 reduced Aβ40 and Aβ42 levels in tris-soluble fractions, with peak reduction at approximately 3h after oral administration in C57BL mice. Moreover, at >1mg/kg, compound-1 dose dependently reduced Aβ40 and Aβ42 levels in Tg2576 mice. Chronic treatment with compound-1 in Tg2576 mice for 4 months significantly reduced both soluble and insoluble Aβ42 levels and ameliorated cognitive impairments, even after drug withdrawal for 10 days following oral administration for 2 months. In contrast with compound-1, at 100-fold higher doses (100mg/kg), the GSI LY450139 decreased HES1 mRNA expression in thymus tissues and increased the intensity of periodic acid-Schiff (PAS)-positive areas in the intestine. Moreover, the Notch-sparing GSI BMS708163 led to amyloid precursor protein (APP)-β-C-terminal fragment accumulation in mouse primary neurons. BMS708163 significantly hampered cognitive function in normal mice 1 month after administration, whereas compound-1 significantly improved cognitive function. Taken together, the present novel and orally active GSM is a promising molecule for the treatment of pathologies associated with Aβ42 and Aβ40.