Aggregation and catabolism of disease-associated intra-Aβ mutations: reduced proteolysis of AβA21G by neprilysin

Five point mutations within the amyloid β-protein (Aβ) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer’s disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Alth...

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Bibliographic Details
Published in:Neurobiology of Disease
Main Authors: Betts, Vicki, Leissring, Malcolm A., Dolios, Georgia, Wang, Rong, Selkoe, Dennis J., Walsh, Dominic M.
Format: Text
Language:English
Published: 2008
Subjects:
Article
Arctic
Online Access:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160758
http://www.ncbi.nlm.nih.gov/pubmed/18602473
https://doi.org/10.1016/j.nbd.2008.06.001
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Summary:Five point mutations within the amyloid β-protein (Aβ) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer’s disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Aβ production, whether or not intra-Aβ mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate.

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