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 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.
Hussain
Ishrut
I
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd., Harlow, UK. Ishrut.2.Hussain@gsk.com
Harrison
David C
DC
Hawkins
Julie
J
Chapman
Trevor
T
Marshall
Ian
I
Facci
Laura
L
Ahmed
Sharlin
S
Brackenborough
Kim
K
Skaper
Stephen D
SD
Mead
Tania L
TL
Smith
Beverley B
BB
Giblin
Gerard M P
GM
Hall
Adrian
A
Gonzalez
M Isabel
MI
Richardson
Jill C
JC
D000085:Acetates / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology*; D053764:Presenilin-1 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D000085:Acetates; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D010880:Piperidines; D053764:Presenilin-1; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases