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Your search keyword '"Amyloid Precursor Protein Secretases"' showing total 2 results
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2 results on '"Amyloid Precursor Protein Secretases"'

1. The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.

Author

Dermaut B, Theuns J, Sleegers K, Hasegawa H, Van den Broeck M, Vennekens K, Corsmit E, St George-Hyslop P, Cruts M, van Duijn CM, and Van Broeckhoven C

Subjects
Age of Onset, Aged, Alleles, Amyloid Precursor Protein Secretases, Apolipoprotein E4, Apolipoproteins E genetics, Aspartic Acid Endopeptidases, Case-Control Studies, Female, Gene Frequency genetics, Genetic Variation genetics, Haplotypes genetics, Humans, Male, Middle Aged, Molecular Sequence Data, Netherlands epidemiology, Odds Ratio, Polymorphism, Single Nucleotide genetics, Alzheimer Disease epidemiology, Alzheimer Disease genetics, Endopeptidases chemistry, Genetic Predisposition to Disease genetics, Membrane Glycoproteins genetics
Abstract

Nicastrin regulates gamma-secretase cleavage of the amyloid precursor protein by forming complexes with presenilins, in which most mutations causing familial early-onset Alzheimer disease (EOAD) have been found. The gene encoding nicastrin (NCSTN) maps to 1q23, a region that has been linked and associated with late-onset Alzheimer disease (LOAD) in various genome screens. In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y). N417Y is unlikely to be pathogenic, since it did not alter amyloid beta secretion in an in vitro assay and its frequency was similar in case and control subjects. However, SNP haplotype estimation in two population-based series of Dutch patients with EOAD (n=116) and LOAD (n=240) indicated that the frequency of one SNP haplotype (HapB) was higher in the group with familial EOAD (7%), compared with the LOAD group (3%) and control group (3%). In patients with familial EOAD without the APOE epsilon4 allele, the HapB frequency further increased, to 14%, resulting in a fourfold increased risk (odds ratio = 4.1; 95% confidence interval 1.2-13.3; P=.01). These results are compatible with an important role of gamma-secretase dysfunction in the etiology of familial EOAD.

Published
2002
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2. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.

Author

Farzan M, Schnitzler CE, Vasilieva N, Leung D, and Choe H

Subjects
Alzheimer Disease genetics, Alzheimer Disease metabolism, Amino Acid Sequence, Amino Acid Substitution genetics, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor genetics, Arginine genetics, Arginine metabolism, Aspartic Acid Endopeptidases chemistry, Aspartic Acid Endopeptidases genetics, Binding Sites, Cell Line, Cloning, Molecular, Endopeptidases, Gene Expression Profiling, Humans, Hydrogen-Ion Concentration, Molecular Sequence Data, Mutation, Missense genetics, Nervous System enzymology, Netherlands, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Phenylalanine metabolism, RNA, Messenger analysis, RNA, Messenger genetics, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Homology, Amino Acid, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Substrate Specificity, Sweden, Amyloid beta-Protein Precursor metabolism, Aspartic Acid Endopeptidases metabolism, Protein Processing, Post-Translational
Abstract

Production of amyloid-beta protein (Abeta) is initiated by a beta-secretase that cleaves the Abeta precursor protein (APP) at the N terminus of Abeta (the beta site). A recently identified aspartyl protease, BACE, cleaves the beta site and at residue 11 within the Abeta region of APP. Here we show that BACE2, a BACE homolog, cleaves at the beta site and more efficiently at a different site within Abeta. The Flemish missense mutation of APP, implicated in a form of familial Alzheimer's disease, is adjacent to this latter site and markedly increases Abeta production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within Abeta by both enzymes. These data suggest that BACE2 contributes to Abeta production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous.

Published
2000
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