Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis

• Published in: Science (American Association for the Advancement of Science) Vol. 323; no. 5920; pp. 1473 - 1477
• Main Authors: Di Fede, Giuseppe, Catania, Marcella, Morbin, Michela, Rossi, Giacomina, Suardi, Silvia, Mazzoleni, Giulia, Merlin, Marco, Giovagnoli, Anna Rita, Prioni, Sara, Erbetta, Alessandra, Falcone, Chiara, Gobbi, Marco, Colombo, Laura, Bastone, Antonio, Beeg, Marten, Manzoni, Claudia, Francescucci, Bruna, Spagnoli, Alberto, Cantù, Laura, Del Favero, Elena, Levy, Efrat, Salmona, Mario, Tagliavini, Fabrizio
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 13.03.2009; The American Association for the Advancement of Science
• Subjects: Adult; Adult and adolescent clinical studies; Aggregation; Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amino Acid Substitution; amyloid; Amyloid - metabolism; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloids; Beta; Biological and medical sciences; Cell aggregates; Cell Line; CHO cells; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - genetics; Dementia - metabolism; Female; Fibroblasts; genes; Genes, Recessive; Genetic mutation; Genetic screening; Genetics; heterozygosity; Heterozygote; homozygosity; Homozygote; Humans; inheritance (genetics); Kinetics; Male; Medical sciences; Mutation; Nervous system diseases; Neurology; Neurotoxicity; Organic mental disorders. Neuropsychology; Pedigree; penetrance; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptides; Protein Binding; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; screening; Solar fibrils; Transfection; Nervous system diseases; Alanine; Peptides; Alzheimer disease; Medical screening; Homozygosity; Genetic determinism; In vitro; Amyloid precursor protein; Protein; Cerebral disorder; Familial disease; Neurotoxicity; Treatment; Valine; Central nervous system disease; Degenerative disease; Mutation; Fibril
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1168979

β-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673[rightward arrow]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. Co-incubation 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.