Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis.
Alzheimer's disease (AD) is characterized by the invariant accumulation of senile plaques predominantly composed of the pathologically relevant 42-amino acid amyloid beta-peptide (Abeta42). The presenilin (PS) proteins play a key role in Abeta generation. FAD-associated mutations in PS1 and PS2 enhance the production of Abeta42, and PS1 is required for physiological Abeta 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 Abeta production. Moreover, when a FAD-associated mutation (M146L) was combined with a mutation blocking endoproteolysis, Abeta42 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.
Steiner
H
H
Department of Molecular Biology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany.
Romig
H
H
Pesold
B
B
Philipp
U
U
Baader
M
M
Citron
M
M
Loetscher
H
H
Jacobsen
H
H
Haass
C
C
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017354:Point Mutation; D053764:Presenilin-1; D014162:Transfection
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D010450:Endopeptidases