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

TY - JOUR

T1 - Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers.

AU - Kaden, Daniela

AU - Harmeier, Anja

AU - Weise, Christoph

AU - Munter, Lisa M

AU - Althoff, Veit

AU - Rost, Benjamin R

AU - Hildebrand, Peter W

AU - Schmitz, Dietmar

AU - Schaefer, Michael

AU - Lurz, Rudi

AU - Skodda, Sabine

AU - Yamamoto, Raina

AU - Arlt, Sönke

AU - Finckh, Ulrich

AU - Multhaup, Gerd

PY - 2012

Y1 - 2012

N2 - 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-? (A?) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the ?-secretase cleavage site and influences both APP and A?. First, due to the K16N mutation APP secretion is affected and a higher amount of A? peptides is being produced. Second, A? 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?42 K16N inhibits fibril formation of A?42 wild-type. Even more, A?42 K16N peptides are protected against clearance activity by the major A?-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.

AB - 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-? (A?) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the ?-secretase cleavage site and influences both APP and A?. First, due to the K16N mutation APP secretion is affected and a higher amount of A? peptides is being produced. Second, A? 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?42 K16N inhibits fibril formation of A?42 wild-type. Even more, A?42 K16N peptides are protected against clearance activity by the major A?-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.

KW - Humans

KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

KW - Mutation

KW - Cell Line, Tumor

KW - Amino Acid Sequence

KW - Molecular Sequence Data

KW - Amino Acid Substitution

KW - Transfection

KW - HEK293 Cells

KW - Amyloid Precursor Protein Secretases/metabolism

KW - Alzheimer Disease/metabolism/pathology

KW - Amyloid beta-Peptides/cerebrospinal fluid/genetics/metabolism

KW - Neprilysin/metabolism

KW - Peptide Fragments/genetics/metabolism

KW - Humans

KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

KW - Mutation

KW - Cell Line, Tumor

KW - Amino Acid Sequence

KW - Molecular Sequence Data

KW - Amino Acid Substitution

KW - Transfection

KW - HEK293 Cells

KW - Amyloid Precursor Protein Secretases/metabolism

KW - Alzheimer Disease/metabolism/pathology

KW - Amyloid beta-Peptides/cerebrospinal fluid/genetics/metabolism

KW - Neprilysin/metabolism

KW - Peptide Fragments/genetics/metabolism

U2 - 10.1002/emmm.201200239

DO - 10.1002/emmm.201200239

M3 - SCORING: Journal article

VL - 4

SP - 647

EP - 659

JO - EMBO MOL MED

JF - EMBO MOL MED

SN - 1757-4676

IS - 7

M1 - 7

ER -