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


  • D. Kaden
  • A. Harmeier
  • C. Weise
  • L.M. Munter
  • V. Althoff
  • B.R. Rost
  • P.W. Hildebrand
  • D. Schmitz
  • M. Schaefer
  • R. Lurz
  • S. Skodda
  • R. Yamamoto
  • S. Arlt
  • U. Finckh
  • G. Multhaup


  • EMBO Molecular Medicine


  • EMBO Mol Med 4 (7): 647-659


  • 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.