title: Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers.
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-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.
authors.affiliation: Institut fuer Chemie und Biochemie, Freie Universitaet, Berlin, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaden
authors.forename: Anja
authors.initials: A
authors.lastname: Harmeier
authors.forename: Christoph
authors.initials: C
authors.lastname: Weise
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Munter
authors.forename: Veit
authors.initials: V
authors.lastname: Althoff
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Rost
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmitz
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.forename: Rudi
authors.initials: R
authors.lastname: Lurz
authors.forename: Sabine
authors.initials: S
authors.lastname: Skodda
authors.forename: Raina
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Sönke
authors.initials: S
authors.lastname: Arlt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Finckh
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D015260:Neprilysin / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D015260:Neprilysin