TY - JOUR
T1 - A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis
AU - Di Fede, Giuseppe
AU - Catania, Marcella
AU - Morbin, Michela
AU - Rossi, Giacomina
AU - Suardi, Silvia
AU - Mazzoleni, Giulia
AU - Merlin, Marco
AU - Giovagnoli, Anna Rita
AU - Prioni, Sara
AU - Erbetta, Alessandra
AU - Falcone, Chiara
AU - Gobbi, Marco
AU - Colombo, Laura
AU - Bastone, Antonio
AU - Beeg, Marten
AU - Manzoni, Claudia
AU - Francescucci, Bruna
AU - Spagnoli, Alberto
AU - Cantù, Laura
AU - Del Favero, Elena
AU - Levy, Efrat
AU - Salmona, Mario
AU - Tagliavini, Fabrizio
PY - 2009/3/13
Y1 - 2009/3/13
N2 - β-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 β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Aβ 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.
AB - β-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 β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Aβ 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.
UR - http://www.scopus.com/inward/record.url?scp=62449330486&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62449330486&partnerID=8YFLogxK
U2 - 10.1126/science.1168979
DO - 10.1126/science.1168979
M3 - Article
C2 - 19286555
AN - SCOPUS:62449330486
VL - 323
SP - 1473
EP - 1477
JO - Science
JF - Science
SN - 0036-8075
IS - 5920
ER -