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Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers

Item Type:Article
Title:Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers
Creators Name:Kaden, D. and Harmeier, A. and Weise, C. and Munter, L.M. and Althoff, V. and Rost, B.R. and Hildebrand, P.W. and Schmitz, D. and Schaefer, M. and Lurz, R. and Skodda, S. and Yamamoto, R. and Arlt, S. and Finckh, U. and Multhaup, G.
Abstract:Here, we describe a novel missense mutation in the amyloid precursor protein (APP) causing a lysine-to-asparagine substitution at position 687 (APP770; herein, referred to as K16N according to amyloid-{beta} (A{beta}) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the {alpha}-secretase cleavage site and influences both APP and A{beta}. First, due to the K16N mutation APP secretion is affected and a higher amount of A{beta} peptides is being produced. Second, A{beta} peptides carrying the K16N mutation are unique in that the peptide itself is not harmful to neuronal cells. Severe toxicity, however, is evident upon equimolar mixture of wt and mutant peptides, mimicking the heterozygous state of the subject. Furthermore, A{beta}42 K16N inhibits fibril formation of A{beta}42 wild-type. Even more, A{beta}42 K16N peptides are protected against clearance activity by the major A{beta}-degrading enzyme neprilysin. Thus the mutation characterized here harbours a combination of risk factors that synergistically may contribute to the development of early onset Alzheimer disease.
Keywords:Aggregation, Alzheimer Disease, Amyloid-Beta Toxicity, APP Processing, Neprilysin
Source:EMBO Molecular Medicine
ISSN:1757-4676
Publisher:Wiley-Blackwell (Germany)
Volume:4
Number:7
Page Range:647-659
Date:July 2012
Official Publication:https://doi.org/10.1002/emmm.201200239
PubMed:View item in PubMed

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