The present address of Eva Czirr is the Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, USA.
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
Article first published online: 13 DEC 2010
© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry
Journal of Neurochemistry
Volume 116, Issue 3, pages 385–395, February 2011
How to Cite
Hahn, S., Brüning, T., Ness, J., Czirr, E., Baches, S., Gijsen, H., Korth, C., Pietrzik, C. U., Bulic, B. and Weggen, S. (2011), 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. Journal of Neurochemistry, 116: 385–395. doi: 10.1111/j.1471-4159.2010.07118.x
- Issue published online: 7 JAN 2011
- Article first published online: 13 DEC 2010
- Accepted manuscript online: 20 NOV 2010 08:20AM EST
- Received September 20, 2010; revised manuscript received November 6, 2010; accepted November 16, 2010.
- γ-secretase modulators;
- familial Alzheimer’s disease;
- amyloid precursor protein;
- transgenic mouse models
J. Neurochem. (2011) 116, 385–395.
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 together, our findings indicate that most AD models with rapid pathology and advanced phenotypes are unsuitable for preclinical GSM studies. However, we also provide evidence that additional compound screens could discover GSMs that are able to break the attenuating effects of PSEN mutations.