Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

Bart De Strooper (), Paul Saftig (), Katleen Craessaerts, Hugo Vanderstichele, Gundula Guhde, Wim Annaert, Kurt Von Figura and Fred Van Leuven
Additional contact information
Bart De Strooper: Experimental Genetics Group, Flemish Institute for Biotechnology (VIB4), Center for Human Genetics
Paul Saftig: Innogenetics NV
Katleen Craessaerts: Experimental Genetics Group, Flemish Institute for Biotechnology (VIB4), Center for Human Genetics
Gundula Guhde: Zentrum Biochemie und Molekular Zellbiologie, Universität Göttingen
Wim Annaert: Experimental Genetics Group, Flemish Institute for Biotechnology (VIB4), Center for Human Genetics
Kurt Von Figura: Zentrum Biochemie und Molekular Zellbiologie, Universität Göttingen
Fred Van Leuven: Experimental Genetics Group, Flemish Institute for Biotechnology (VIB4), Center for Human Genetics

Nature, 1998, vol. 391, issue 6665, 387-390

Abstract: 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.

Date: 1998
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DOI: 10.1038/34910

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