An Increased Percentage of Long Amyloid β Protein Secreted by Familial Amyloid β Protein Precursor (βApp 717 ) Mutants
- 27 May 1994
- journal article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 264 (5163) , 1336-1340
- https://doi.org/10.1126/science.8191290
Abstract
Normal processing of the amyloid beta protein precursor (beta APP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or the beta APP717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the A beta in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate A beta 1-40 from the longer A beta 1-42. Both methods demonstrated that the 4-kilodalton A beta released from wild-type beta APP is primarily but not exclusively A beta 1-40. The beta APP717 mutations, which are located three residues carboxyl to A beta 43, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer A beta generated. Long A beta (for example, A beta 1-42) forms insoluble amyloid fibrils more rapidly than A beta 1-40. Thus, the beta APP717 mutants may cause Alzheimer's disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.Keywords
This publication has 41 references indexed in Scilit:
- Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril proteinPublished by Elsevier ,2004
- Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.Proceedings of the National Academy of Sciences, 1993
- Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset FamiliesScience, 1993
- The carboxy terminus of the .beta. amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's diseaseBiochemistry, 1993
- Mapping of a gene predisposing to early–onset Alzheimer's disease to chromosome 14q24.3Nature Genetics, 1992
- A mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's DiseaseScience, 1991
- The 717Val→Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groupsBiochemical and Biophysical Research Communications, 1991
- Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's diseaseJournal of Molecular Biology, 1991
- Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's diseaseNature, 1991
- THE TOPOGRAPHY OF PLAQUES AND TANGLES IN DOWN'S SYNDROME PATIENTS OF DIFFERENT AGESNeuropathology and Applied Neurobiology, 1986