The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
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- 20 August 2001
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 4 (9), 887-893
- https://doi.org/10.1038/nn0901-887
Abstract
Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid β-protein (Aβ) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Aβ sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Aβ42 and Aβ40 levels in plasma. Additionally, low levels of Aβ42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Aβ with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Aβ. The finding of increased protofibril formation and decreased Aβ plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Aβ protofibril formation leading to accelerated buildup of insoluble Aβ intra- and/or extracellularly.Keywords
This publication has 38 references indexed in Scilit:
- Translating cell biology into therapeutic advances in Alzheimer's diseaseNature, 1999
- Flemish and Dutch Mutations in Amyloid β Precursor Protein Have Different Effects on Amyloid β SecretionNeurobiology of Disease, 1998
- Amyloid, the presenilins and Alzheimer's diseaseTrends in Neurosciences, 1997
- Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's diseaseNature Medicine, 1996
- Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation.Proceedings of the National Academy of Sciences of the United States of America, 1994
- Increased β‐amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the Swedish Alzheimer's disease APP670/671 mutationFEBS Letters, 1994
- Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursorOnline Journal of Public Health Informatics, 1994
- A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloidNature Genetics, 1992
- Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β–amyloid precursor protein geneNature Genetics, 1992
- Mutation of the Alzheimer's Disease Amyloid Gene in Hereditary Cerebral Hemorrhage, Dutch TypeScience, 1990