A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.
beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.
Di Fede
Giuseppe
G
Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
Catania
Marcella
M
Morbin
Michela
M
Rossi
Giacomina
G
Suardi
Silvia
S
Mazzoleni
Giulia
G
Merlin
Marco
M
Giovagnoli
Anna Rita
AR
Prioni
Sara
S
Erbetta
Alessandra
A
Falcone
Chiara
C
Gobbi
Marco
M
Colombo
Laura
L
Bastone
Antonio
A
Beeg
Marten
M
Manzoni
Claudia
C
Francescucci
Bruna
B
Spagnoli
Alberto
A
Cantù
Laura
L
Del Favero
Elena
E
Levy
Efrat
E
Salmona
Mario
M
Tagliavini
Fabrizio
F
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007700:Kinetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D014162:Transfection
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)