The Molecular Genetics of Alzheimer's Disease

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 1994 Aug 1

PMID 7888092

Citations 6

Authors

M Mullan

F Crawford

Affiliations

Soon will be listed here.

Abstract

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of beta-amyloid peptide (A beta) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for beta-amyloid precursor protein (beta APP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the beta APP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the beta APP mutations cause the disease and discuss recent advances in beta APP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of the APOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of beta APP and its derivatives.

Citing Articles

Ethyl Acetate Fraction from Persimmon () Ameliorates Cerebral Neuronal Loss and Cognitive Deficit via the JNK/Akt Pathway in TMT-Induced Mice.

Kim J, Park S, Kang J, Park S, Yoo S, Han H Int J Mol Sci. 2018; 19(5).

PMID: 29772805 PMC: 5983595. DOI: 10.3390/ijms19051499.

Ovarian steroids regulate gene expression related to DNA repair and neurodegenerative diseases in serotonin neurons of macaques.

Bethea C, Reddy A Mol Psychiatry. 2015; 20(12):1565-78.

PMID: 25600110 PMC: 4508249. DOI: 10.1038/mp.2014.178.

Differential effect of amyloid β on the cytochrome P450 epoxygenase activity in rat brain.

Sarkar P, Narayanan J, Harder D Neuroscience. 2011; 194:241-9.

PMID: 21843605 PMC: 3183272. DOI: 10.1016/j.neuroscience.2011.07.058.

Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease.

Blalock E, Buechel H, Popovic J, Geddes J, Landfield P J Chem Neuroanat. 2011; 42(2):118-26.

PMID: 21756998 PMC: 3163806. DOI: 10.1016/j.jchemneu.2011.06.007.

Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses.

Blalock E, Geddes J, Chen K, Porter N, Markesbery W, Landfield P Proc Natl Acad Sci U S A. 2004; 101(7):2173-8.

PMID: 14769913 PMC: 357071. DOI: 10.1073/pnas.0308512100.

References

Sorbi S, Nacmias B, Forleo P, Piacentini S, Amaducci L, Provinciali L . APP717 and Alzheimer's disease in Italy. Nat Genet. 1993; 4(1):10. DOI: 10.1038/ng0593-10. View

Chartier-Harlin M, Crawford F, Houlden H, Warren A, Hughes D, Fidani L . Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991; 353(6347):844-6. DOI: 10.1038/353844a0. View

Golde T, Estus S, Younkin L, Selkoe D, Younkin S . Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science. 1992; 255(5045):728-30. DOI: 10.1126/science.1738847. View

Strittmatter W, Weisgraber K, Huang D, Dong L, Salvesen G, Pericak-Vance M . Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90(17):8098-102. PMC: 47295. DOI: 10.1073/pnas.90.17.8098. View

Strittmatter W, Saunders A, Schmechel D, Pericak-Vance M, Enghild J, Salvesen G . Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90(5):1977-81. PMC: 46003. DOI: 10.1073/pnas.90.5.1977. View

Seubert P, Oltersdorf T, Lee M, Barbour R, Blomquist C, Davis D . Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature. 1993; 361(6409):260-3. DOI: 10.1038/361260a0. View

Tanzi R, Gusella J, Watkins P, BRUNS G, St George-Hyslop P, Van Keuren M . Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987; 235(4791):880-4. DOI: 10.1126/science.2949367. View

Schellenberg G, Bird T, Wijsman E, Moore D, Boehnke M, Bryant E . Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease. Science. 1988; 241(4872):1507-10. DOI: 10.1126/science.3420406. View

Pericak-Vance M, Bebout J, Gaskell Jr P, Yamaoka L, Hung W, Alberts M . Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet. 1991; 48(6):1034-50. PMC: 1683100. View

10.

Davignon J, GREGG R, Sing C . Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988; 8(1):1-21. DOI: 10.1161/01.atv.8.1.1. View

11.

Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y . The 717Val----Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem Biophys Res Commun. 1991; 178(3):1141-6. DOI: 10.1016/0006-291x(91)91011-z. View

12.

Shoji M, Golde T, Ghiso J, Cheung T, Estus S, Shaffer L . Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992; 258(5079):126-9. DOI: 10.1126/science.1439760. View

13.

St George-Hyslop P, Haines J, Farrer L, Polinsky R, Van Broeckhoven C, Goate A . Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder. Nature. 1990; 347(6289):194-7. DOI: 10.1038/347194a0. View

14.

Van Broeckhoven C, Genthe A, Vandenberghe A, Horsthemke B, Backhovens H, Raeymaekers P . Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families. Nature. 1987; 329(6135):153-5. DOI: 10.1038/329153a0. View

15.

Mullan M, Houlden H, Crawford F, Kennedy A, Rogues P, Rossor M . Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology. Am J Med Genet. 1993; 48(3):129-30. DOI: 10.1002/ajmg.1320480303. View

16.

Marx J . Alzheimer's pathology begins to yield its secrets. Science. 1993; 259(5094):457-8. DOI: 10.1126/science.8424167. View

17.

Gandy S, Czernik A, Greengard P . Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II. Proc Natl Acad Sci U S A. 1988; 85(16):6218-21. PMC: 281937. DOI: 10.1073/pnas.85.16.6218. View

18.

Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B . A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992; 1(5):345-7. DOI: 10.1038/ng0892-345. View

19.

Levy E, Carman M, Power M, Lieberburg I, van Duinen S, BOTS G . Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990; 248(4959):1124-6. DOI: 10.1126/science.2111584. View

20.

Mullan M, Tsuji S, Miki T, Katsuya T, Naruse S, Kaneko K . Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val-->Ile mutation in the amyloid precursor protein gene. Neurobiol Aging. 1993; 14(5):407-19. DOI: 10.1016/0197-4580(93)90099-w. View