Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers.
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Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers. / 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.
In: EMBO MOL MED, Vol. 4, No. 7, 7, 2012, p. 647-659.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -