ABSTRACT
BACKGROUND: Cleavage of the amyloid precursor protein (APP) by ß-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-ß (Aß) 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 Aß42 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 Aß peptides to induce neurotoxicity in rat primary cortical neurons. METHODS: The effect of GSM-10h on Aß 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 Aß42 while concomitantly increasing levels of Aß38 in the absence of effects on Aß40 levels. In TASTPM mice, GSM-10h effectively lowered brain Aß42 and increased brain Aß38, with no effect on Notch signalling. Unlike Aß42, which causes neuronal cell death, neither Aß37 nor Aß38 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.
Subject(s)
Acetates/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Protein Precursor/biosynthesis , Peptide Fragments/antagonists & inhibitors , Piperidines/pharmacology , Presenilin-1/biosynthesis , Amyloid beta-Protein Precursor/genetics , Animals , Cell Death/drug effects , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/pathology , Presenilin-1/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Transgenes/geneticsABSTRACT
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
