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Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer’s disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure: γ-Secretase modulators and familial Alzheimer’s disease mutations

Hahn, Stefanie, Brüning, Tanja, Ness, Julia, Czirr, Eva, Baches, Sandra, Gijsen, Harrie, Korth, Carsten, Pietrzik, Claus U., Bulic, Bruno, Weggen, Sascha·2011·Journal of Neurochemistry
DOI 10.1111/j.1471-4159.2010.07118.x
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Abstract

γ-Secretase modulators (GSMs) inhibit the generation of amyloidogenic Aβ42 peptides and are promising agents for treatment or prevention of Alzheimer's disease (AD). Recently, a second generation of GSMs with favorable pharmacological properties has emerged, but preclinical studies to assess their efficacy in vivo are lacking. Such studies rely on transgenic mouse models that express amyloid precursor protein (APP) and presenilin (PSEN) mutations associated with early-onset familial AD. Previously, we have shown that certain PSEN1 mutations attenuated the response of cultured cells to GSMs and potentially confound in vivo studies in AD mouse models. However, different combinations of familial AD mutations might have synergistic or opposing effects, and we have now systematically determined the response of APP and PSEN1 mutations present in current AD models. Using a potent acidic GSM, we found that APP mutations, either single mutations or in combination, did not affect the potency of GSMs. In contrast, all PSEN1 mutations that have been used to accelerate pathological changes in AD models strongly attenuated the Aβ42-lowering activity of GSMs with two exceptions (M146L, A246E). Similar results were obtained with potent non-acidic GSMs indicating that the attenuating effect of PSEN1 mutations cannot simply be overcome by increased potency or structural changes. Notably, two non-acidic compounds fully compensated the attenuating effect of the PSEN1-G384A mutation. Taken togeth…

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Metadata

Authors
Hahn, S., Brüning, T., Ness, J., Czirr, E., Baches, S., Gijsen, H., Korth, C., Pietrzik, C. U., Bulic, B., & Weggen, S.
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2010-12-13
Volume
116
Issue
3
Pages
385-395
ISSN
0022-3042
DOI
10.1111/j.1471-4159.2010.07118.x
Cited by
42
References
10
Language
en
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1723 d)

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