Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease.
We have identified a novel beta amyloid precursor protein (betaAPP) mutation (V715M-betaAPP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked betaAPP mutations reported to date, overexpression of V715M-betaAPP in human HEK293 cells and murine neurons reduces total Abeta production and increases the recovery of the physiologically secreted product, APPalpha. V715M-betaAPP significantly reduces Abeta40 secretion without affecting Abeta42 production in HEK293 cells. However, a marked increase in N-terminally truncated Abeta ending at position 42 (x-42Abeta) is observed, whereas its counterpart x-40Abeta is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of Abeta but may be caused by increased production of truncated forms of Abeta ending at the 42 position.
Ancolio
K
K
Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, UPR 411, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
Dumanchin
C
C
Barelli
H
H
Warter
J M
JM
Brice
A
A
Campion
D
D
Frébourg
T
T
Checler
F
F
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008715:Methionine; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014633:Valine
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D008715:Methionine; D014633:Valine