Journal ArticleDOI
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
Alison Goate,Marie-Christine Chartier-Harlin,Michael Mullan,Jeremy P Brown,Fiona Crawford,Liana Fidani,L. Giuffra,Andrew Haynes,N.G. Irving,Louise James,R. Mant,Phillippa Newton,Karen Rooke,P Roques,Christopher Talbot,Margaret A. Pericak-Vance,Alien D. Roses,Robert Williamson,Martin N. Rossor,Michael John Owen,John Hardy +20 more
TLDR
A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene as discussed by the authors, which suggests that some cases of AD could be caused by mutations in the APP gene.Abstract:
A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.read more
Citations
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Journal ArticleDOI
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Journal ArticleDOI
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Elizabeth H. Corder,Ann M. Saunders,Warren J. Strittmatter,Donald E. Schmechel,P. C. Gaskell,Gary W. Small,A. D. Roses,Jonathan L. Haines,Margaret A. Pericak-Vance +8 more
TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Journal ArticleDOI
Alzheimer's disease: the amyloid cascade hypothesis
John Hardy,Gerald A. Higgins +1 more
TL;DR: An extensive catalog of genes that act in a migrating cell is provided, unique molecular functions involved in nematode cell migration are identified, and similar functions in humans are suggested.
Journal ArticleDOI
Alzheimer's Disease: Genes, Proteins, and Therapy
TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Journal ArticleDOI
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
Christian Haass,Dennis J. Selkoe +1 more
TL;DR: Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
References
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Journal ArticleDOI
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