Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis

Biochemistry 38(44): 14600-5

Authors/Editors: Steiner H
Romig H
Pesold B
Philipp U
Baader M
Citron M
Loetscher H
Jacobsen H
Haass C
Publication Date: 1999
Type of Publication: Journal Article

Alzheimer's disease (AD) is characterized by the invariant accumulation of senile plaques predominantly composed of the pathologically relevant 42-amino acid amyloid β-peptide (Aβ42). The presenilin (PS) proteins play a key role in Aβ generation. FAD-associated mutations in PS1 and PS2 enhance the production of Aβ42, and PS1 is required for physiological Aβ production, since a gene knockout of PS1 and dominant negative mutations of PS1 abolish Abeta generation. PS proteins undergo endoproteolytic processing, and current evidence indicates that fragment formation may be required for the amyloidogenic function of PS. We have now determined the sequence requirements for endoproteolysis of PS1. Mutagenizing amino acids at the previously determined major cleavage site (amino acid 298) had no effect on PS1 endoproteolysis. In contrast, mutations or deletions at the additional cleavage site around amino acid 292 blocked endoproteolysis. The uncleavable PS1 derivatives accumulated as full-length proteins and replaced the endogenous PS1 proteins. In contrast to the previously described aspartate mutations within transmembrane domains 6 and 7, the uncleaved PS1 variants do not act as dominant negative inhibitors of Aβ production. Moreover, when a FAD-associated mutation (M146L) was combined with a mutation blocking endoproteolysis, Aβ42 production still reached pathological levels. These data therefore demonstrate that endoproteolysis of presenilins is not an absolute prerequisite for the amyloidogenic function of PS1. These data also show that accumulation of the PS1 holoprotein is not associated with the pathological activity of PS1 mutations as suggested previously.

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