MUTATION OF THE BETA-AMYLOID PRECURSOR PROTEIN IN FAMILIAL ALZHEIMERS-DISEASE INCREASES BETA-PROTEIN PRODUCTION

PROGRESSIVE cerebral deposition of the 39-43-amino-acid amyloid beta-protein (Abeta) 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 beta-amyloid precursor protein (beta-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 Abeta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated Abeta deposition is unknown. Here we report that cultured cells which express a beta-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 approximate 6-8-fold more Abeta than cells expressing normal beta-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 relevance of the continuous Abeta production by cultured cells6-8 for elucidating the fundamental mechanism of Alzheimer's disease.