Publication Date:
1994-05-27
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suzuki, N -- Cheung, T T -- Cai, X D -- Odaka, A -- Otvos, L Jr -- Eckman, C -- Golde, T E -- Younkin, S G -- AG06656/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 1994 May 27;264(5163):1336-40.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Discovery Research Division, Takeda Chemical Industries, Ltd., Ibaraki, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8191290" target="_blank"〉PubMed〈/a〉
Keywords:
Alzheimer Disease/genetics
;
Amyloid beta-Peptides/chemistry/*secretion
;
Amyloid beta-Protein Precursor/chemistry/genetics/*metabolism
;
Culture Media, Conditioned
;
Enzyme-Linked Immunosorbent Assay
;
Humans
;
*Mutation
;
Neuroblastoma
;
Transfection
;
Tumor Cells, Cultured
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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