Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production

• Published in: Nature (London) 1992-12, Vol.360 (6405), p.672-674
• Main Authors: Citron, Martin, Oltersdorf, Tilman, Haass, Christian, McConlogue, Lisa, Hung, Albert Y, Seubert, Peter, Vigo-Pelfrey, Carmen, Lieberburg, Ivan, Selkoe, Dennis J
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Protein Precursor - genetics; Base Sequence; Biological and medical sciences; Cell Line; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia disorders; Genetics; Humanities and Social Sciences; Humans; Kidney; letter; Medical research; Medical sciences; Molecular Sequence Data; multidisciplinary; Mutation; Neurology; Oligodeoxyribonucleotides; Proteins; Restriction Mapping; Science; Science (multidisciplinary); Sweden; Transfection
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/360672a0

PROGRESSIVE cerebral deposition of the 39–43-amino-acid amy-loid β-protein (Aβ) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the β-amyloid precursor protein (β3-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD) 1–5 . These mutations are located within or immediately flanking the Aβ region of β-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated Aβ deposition is unknown. Here we report that cultured cells which express a β-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family5 produce ∼6–8-fold more Aβ than cells expressing normal β-APP. The Met 596 to Leu mutation is principally responsible for the increase. These data establish a direct link between a FAD genotype and the clinicopathological phenotype. Further, they confirm the relev-ance of the continuous Aβ production by cultured cells 6–8 for elucidating the fundamental mechanism of Alzheimer's disease.