title: A megalin polymorphism associated with promoter activity and Alzheimer's disease risk.
abstract: Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.
authors.affiliation: Neuroscience Laboratory, Research Center, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Teo
authors.initials: T
authors.lastname: Vargas
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez-Garcia
authors.forename: Desiree
authors.initials: D
authors.lastname: Antequera
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimon
authors.forename: Marcel
authors.initials: M
authors.lastname: Rosich-Estrago
authors.forename: Angeles
authors.initials: A
authors.lastname: Martin-Requero
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mateo
authors.forename: Eloy
authors.initials: E
authors.lastname: Rodriguez-Rodriguez
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella-Cuadrada
authors.forename: Ana
authors.initials: A
authors.lastname: Frank
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleo
authors.forename: Laura
authors.initials: L
authors.lastname: Molina-Porcel
authors.forename: Rafael
authors.initials: R
authors.lastname: Blesa
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
authors.forename: Teresa
authors.initials: T
authors.lastname: Gomez-Isla
authors.forename: Felix
authors.initials: F
authors.lastname: Bermejo-Pareja
authors.forename: Fernando
authors.initials: F
authors.lastname: Valdivieso
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D005796:Genes; D005838:Genotype; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000276:immunology; D008297:Male; D015337:Multicenter Studies as Topic; D011110:Polymorphism, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012307:Risk Factors
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D026561:Low Density Lipoprotein Receptor-Related Protein-2