Open AccessNovel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers
Author(s) -
Kaden Daniela,
Harmeier Anja,
Weise Christoph,
Munter Lisa M.,
Althoff Veit,
Rost Benjamin R.,
Hildebrand Peter W.,
Schmitz Dietmar,
Schaefer Michael,
Lurz Rudi,
Skodda Sabine,
Yamamoto Raina,
Arlt Sönke,
Finckh Ulrich,
Multhaup Gerd
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200239
Subject(s) - mutation , chemistry , microbiology and biotechnology , computational biology , biology , biochemistry , gene
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‐β (Aβ) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the α‐secretase cleavage site and influences both APP and Aβ. First, due to the K16N mutation APP secretion is affected and a higher amount of Aβ peptides is being produced. Second, Aβ 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, Aβ42 K16N inhibits fibril formation of Aβ42 wild‐type. Even more, Aβ42 K16N peptides are protected against clearance activity by the major Aβ‐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.