Abstract
The β-amyloid precursor protein (β-APP), which is involved in the pathogenesis of Alzheimer’s disease, and the Notch receptor, which is responsible for critical signalling events during development, both undergo unusual proteolysis within their transmembrane domains by unknown γ-secretases. Here we show that an affinity reagent designed to interact with the active site of γ-secretase binds directly and specifically to heterodimeric forms of presenilins, polytopic proteins that are mutated in hereditary Alzheimer’s and are known mediators of γ-secretase cleavage of both β-APP and Notch. These results provide evidence that heterodimeric presenilins contain the active site of γ-secretase, and validate presenilins as principal targets for the design of drugs to treat and prevent Alzheimer’s disease.
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Acknowledgements
We thank D. Miller and D. Walsh for helpful discussions, W. Ye for help with cell cultures, J. Shen for providing PS1–/– mouse fibroblasts, S. Gandy for antibody Ab14, C. Haass for antibody 2972 and T. Iwatsubo for antibody PS2L. This work was supported by NIH grants NS37537 (to M.S.W.) and AG12749 (to D.J.S.) and by a Pioneer Award from the Alzheimer’s Association (to D.J.S.).
Correspondence and requests for materials should be addressed to M.S.W.
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Esler, W., Kimberly, W., Ostaszewski, B. et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol 2, 428–434 (2000). https://doi.org/10.1038/35017062
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DOI: https://doi.org/10.1038/35017062
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