TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to γ-secretase modulation and amyloid-β₄₂ lowering by GSM-10h.
| Autor: | Hussain I; Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd., Harlow, UK. Ishrut.2.Hussain@gsk.com, Harrison DC, Hawkins J, Chapman T, Marshall I, Facci L, Ahmed S, Brackenborough K, Skaper SD, Mead TL, Smith BB, Giblin GM, Hall A, Gonzalez MI, Richardson JC |
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| Jazyk: | angličtina |
| Zdroj: | Neuro-degenerative diseases [Neurodegener Dis] 2011; Vol. 8 (1-2), pp. 15-24. Date of Electronic Publication: 2010 Aug 04. |
| DOI: | 10.1159/000313903 |
| Abstrakt: | 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. (Copyright © 2010 S. Karger AG, Basel.) |
| Databáze: | MEDLINE |
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