Abstract
Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-β(1–42) by proteolytic processing of the amyloid precursor protein (APP)1,2,3,4. Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by α- and β-secretase5 of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by γ-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor6, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
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Acknowledgements
This work was supported by the FWO-Vlaanderen, the Flemish Action Program for Biotechnology (VLAB), the Flemish Institute for Biotechnology (VIB), the K.U.Leuven, the Human Frontier of Science Program (HFSP), the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. We thank B. Greenberg for antibodies anti-APP1-612 and anti-APPKM595/596, D. Selkoe for R1736 and R1282, and F. Checler for FCA3340, C. Dotti, B. Nelissen and E.Vanmechelen for advice; and S. Tiereliers for technical assistance.
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De Strooper, B., Saftig, P., Craessaerts, K. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998). https://doi.org/10.1038/34910
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DOI: https://doi.org/10.1038/34910
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