title: A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.
abstract: 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.
authors.affiliation: Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.forename: Marcella
authors.initials: M
authors.lastname: Catania
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.forename: Silvia
authors.initials: S
authors.lastname: Suardi
authors.forename: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Marco
authors.initials: M
authors.lastname: Merlin
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Giovagnoli
authors.forename: Sara
authors.initials: S
authors.lastname: Prioni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Erbetta
authors.forename: Chiara
authors.initials: C
authors.lastname: Falcone
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Antonio
authors.initials: A
authors.lastname: Bastone
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.forename: Bruna
authors.initials: B
authors.lastname: Francescucci
authors.forename: Alberto
authors.initials: A
authors.lastname: Spagnoli
authors.forename: Laura
authors.initials: L
authors.lastname: Cantù
authors.forename: Elena
authors.initials: E
authors.lastname: Del Favero
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: 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
chemical_list: 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)