An Increased Percentage of Long Amyloid β Protein Secreted by Familial Amyloid β Protein Precursor (βApp 717 ) Mutants

American Association for the Advancement of Science (AAAS) - Tập 264 Số 5163 - Trang 1336-1340 - 1994
Nobuhiro Suzuki1, Tobun T. Cheung2, Xiao-Dan Cai2, Asano Odaka1, László Ötvös3, Christopher B. Eckman2, Todd E. Golde2, Steven G. Younkin2
1Discovery Research Division, Takeda Chemical Industries, Ltd., Ibaraki, Japan.
2Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA
3Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA

Tóm tắt

Normal processing of the amyloid β protein precursor (βAPP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid β protein (Aβ) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type βAPP or the βAPP 717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton Aβ from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the Aβ in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate Aβ 1-40 from the longer Aβ 1-42 . Both methods demonstrated that the 4-kilodalton Aβ released from wild-type βAPP is primarily but not exclusively Aβ 1-40 . The βAPP 717 mutations, which are located three residues carboxyl to Aβ 43 , consistently caused a 1.5- to 1.9-fold increase in the percentage of longer Aβ generated. Long Aβ (for example, Aβ 1-42 ) forms insoluble amyloid fibrils more rapidly than Aβ 1-40 . Thus, the βAPP 717 mutants may cause Alzheimer's disease because they secrete increased amounts of long Aβ, thereby fostering amyloid deposition.

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Tài liệu tham khảo

ANWAR, N, LANCET 342: 1308 (1993).

BORGAONKAR, D.S., LINKAGE OF LATE-ONSET ALZHEIMERS-DISEASE WITH APOLIPOPROTEIN-E TYPE-4 ON CHROMOSOME-19, LANCET 342: 625 (1993).

BURDICK, D, ASSEMBLY AND AGGREGATION PROPERTIES OF SYNTHETIC ALZHEIMERS A4/BETA AMYLOID PEPTIDE ANALOGS, JOURNAL OF BIOLOGICAL CHEMISTRY 267: 546 (1992).

10.1126/science.8424174

10.1038/353844a0

CHEUNG T.T. unpublished data.

10.1038/360672a0

10.1126/science.8346443

CZECH, C, LANCET 342: 1310 (1993).

DOVEY, H.F., CELLS WITH A FAMILIAL ALZHEIMERS-DISEASE MUTATION PRODUCE AUTHENTIC BETA-PEPTIDE, NEUROREPORT 4: 1039 (1993).

10.1016/0006-291X(84)91209-9

10.1038/349704a0

10.1126/science.3810169

HARDY, J, MOLECULAR CLASSIFICATION OF ALZHEIMERS-DISEASE, LANCET 337: 1342 (1991).

10.1016/0140-6736(93)91728-5

10.1016/0022-2836(91)90881-6

HYSLOP, P.S., NAT GENET 2: 330 (1992).

10.1021/bi00069a001

10.1016/0092-8674(93)90635-4

10.1038/325733a0

KONIG, G, IDENTIFICATION AND DIFFERENTIAL EXPRESSION OF A NOVEL ALTERNATIVE SPLICE ISOFORM OF THE BETA-A4 AMYLOID PRECURSOR PROTEIN (APP) MESSENGER-RNA IN LEUKOCYTES AND BRAIN MICROGLIAL CELLS, JOURNAL OF BIOLOGICAL CHEMISTRY 267: 10804 (1992).

LUCOTTE, G, APOLIPOPROTEIN-E-SIGMA-4 ALLELE AND ALZHEIMERS-DISEASE, LANCET 342: 1309 (1993).

MANN, DMA, THE TOPOGRAPHY OF PLAQUES AND TANGLES IN DOWNS-SYNDROME PATIENTS OF DIFFERENT AGES, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 12: 447 (1986).

10.1073/pnas.82.12.4245

10.1038/ng0892-345

MULLAN, M, A LOCUS FOR FAMILIAL EARLY-ONSET ALZHEIMERS-DISEASE ON THE LONG ARM OF CHROMOSOME 14, PROXIMAL TO THE ALPHA-1-ANTICHYMOTRYPSIN GENE, NATURE GENETICS 2: 340 (1992).

10.1126/science.1925564

NARUSE, S, MIS-SENSE MUTATION VAL-]ILE IN EXON-17 OF AMYLOID PRECURSOR PROTEIN GENE IN JAPANESE FAMILIAL ALZHEIMERS-DISEASE, LANCET 337: 978 (1991).

10.1016/0140-6736(93)91728-5

OTVOS, L, HUMAN AND RODENT ALZHEIMER BETA-AMYLOID PEPTIDES ACQUIRE DISTINCT CONFORMATIONS IN MEMBRANE-MIMICKING SOLVENTS, EUROPEAN JOURNAL OF BIOCHEMISTRY 211: 249 (1993).

PAYAMI, H, APOLIPOPROTEIN-E GENOTYPE AND ALZHEIMERS-DISEASE, LANCET 342: 738 (1993).

PERICAKVANCE, M.A., LINKAGE STUDIES IN FAMILIAL ALZHEIMER-DISEASE - EVIDENCE FOR CHROMOSOME-19 LINKAGE, AMERICAN JOURNAL OF HUMAN GENETICS 48: 1034 (1991).

POIRIER, J, APOLIPOPROTEIN-E POLYMORPHISM AND ALZHEIMERS-DISEASE, LANCET 342: 697 (1993).

PRELLI, F, DIFFERENCES BETWEEN VASCULAR AND PLAQUE CORE AMYLOID IN ALZHEIMERS-DISEASE, JOURNAL OF NEUROCHEMISTRY 51: 648 (1988).

ROBAKIS, N.K., CHROMOSOME 21Q21 SUBLOCALIZATION OF GENE ENCODING BETA-AMYLOID PEPTIDE IN CEREBRAL VESSELS AND NEURITIC (SENILE) PLAQUES OF PEOPLE WITH ALZHEIMER-DISEASE AND DOWN-SYNDROME, LANCET 1: 384 (1987).

ROPPER, A.H., RELATIONSHIP BETWEEN PLAQUES, TANGLES, AND DEMENTIA IN DOWN SYNDROME, NEUROLOGY 30: 639 (1980).

SAUNDERS, A.M., APOLIPOPROTEIN-E-EPSILON-4 ALLELE DISTRIBUTIONS IN LATE-ONSET ALZHEIMERS-DISEASE AND IN OTHER AMYLOID-FORMING DISEASES, LANCET 342: 710 (1993).

10.1212/WNL.43.8.1467

10.1126/science.1411576

SCHMECHEL, D.E., 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 OF THE UNITED STATES OF AMERICA 90: 9649 (1993).

SELKOE, D.J., ISOLATION OF LOW-MOLECULAR-WEIGHT PROTEINS FROM AMYLOID PLAQUE FIBERS IN ALZHEIMERS-DISEASE, JOURNAL OF NEUROCHEMISTRY 46: 1820 (1986).

10.1126/science.1439760

10.1073/pnas.90.17.8098

Suzuki, N., American Journal of Pathology. 145: 452 (1994).

SUZUKI, N, PRODUCTION OF IMMUNOREACTIVE PITUITARY ADENYLATE-CYCLASE ACTIVATING POLYPEPTIDE (PACAP) BY HUMAN NEUROBLASTOMA-CELLS, IMR-32 - DETECTION AND CHARACTERIZATION WITH MONOCLONAL AND POLYCLONAL ANTIBODIES AGAINST DIFFERENT EPITOPES OF PACAP, JOURNAL OF BIOCHEMISTRY 113: 549 (1993).

SUZUKI, N, A SENSITIVE SANDWICH-ENZYME IMMUNOASSAY FOR HUMAN ENDOTHELIN, JOURNAL OF IMMUNOLOGICAL METHODS 118: 245 (1989).

10.1126/science.2949367

VANBROECKHOVEN, C, MAPPING OF A GENE PREDISPOSING TO EARLY-ONSET ALZHEIMERS-DISEASE TO CHROMOSOME 14Q24.3, NATURE GENETICS 2: 335 (1992).

YOSHIOKA, K, THE 717VAL-]ILE SUBSTITUTION IN AMYLOID PRECURSOR PROTEIN IS ASSOCIATED WITH FAMILIAL ALZHEIMERS-DISEASE REGARDLESS OF ETHNIC-GROUPS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 178: 1141 (1991).

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American Association for the Advancement of Science (AAAS)

Tập 264 Số 5163

1336-1340

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