title: Chinese Presenilin-1 V97L mutation enhanced Abeta42 levels in SH-SY5Y neuroblastoma cells.
abstract: Presenilin-1 gene mutations have been proven to be associated with the majority of early-onset familial Alzheimer's disease (FAD). There have been, however, no systematic studies of Presenilin-1 gene mutation in FAD in China so far. We found a novel Val-->Leu missense mutation at codon 97 (Val97Leu) of the Presenilin-1 gene in a Chinese FAD pedigree. To verify whether this mutation is pathologically functional, we established mutation type and wild type Presenilin-1 gene stably transfected cell lines (human neuroblastoma SH-SY5Y cells) to detect beta-amyloid (Abeta) concentrations using ELISA and radioimmunity methods. We also examined levels of beta-amyloid precursor protein cleaving enzyme (BACE) and amyloid precursor protein (APP) to explore their impact upon beta-amyloid production. Our results showed that Abeta42 concentration was significantly enhanced at 48h when compared to that at 24h in the mutant type cells. At 48h Abeta42 levels in the V97L mutants was also found to be elevated significantly, both intracellularly and extracellularly when compared to wild and mock transfected cells. The total Abeta in either group did not alter, consistent with unchanged BACE and APP expression levels. Our data reveal that the Presenilin-1 V97L variant can elevate Abeta42 levels both intracellularly and extracellularly, and was a potentially pathogenic mutation for this Chinese FAD pedigree. It also suggests that there are common mechanisms in the pathogenesis of FAD between Chinese and other ethnic populations, although their gene mutation sites are different.
authors.affiliation: Department of Neurology, Xuanwu Hospital of the Capital University of Medical Sciences, Neurodegenerative Lab of Ministry of Education of the People's Republic of China, Beijing 100053, PR China.
authors.forename: Boyan
authors.initials: B
authors.lastname: Fang
authors.forename: Longfei
authors.initials: L
authors.lastname: Jia
authors.forename: Jianping
authors.initials: J
authors.lastname: Jia
mesh_terms: D000544:Alzheimer Disease / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D010450:Endopeptidases / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis*; D053764:Presenilin-1; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human