title: Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells.
abstract: Predisposition to sporadic Alzheimer's disease (SAD) involves interactions between a person's unique combination of genetic variants and the environment. The molecular effect of these variants may be subtle and difficult to analyze with standard in vitro or in vivo models. Here we used hIPSCs to examine genetic variation in the SORL1 gene and possible contributions to SAD-related phenotypes in human neurons. We found that human neurons carrying SORL1 variants associated with an increased SAD risk show a reduced response to treatment with BDNF, at the level of both SORL1 expression and APP processing. shRNA knockdown of SORL1 demonstrates that the differences in BDNF-induced APP processing between genotypes are dependent on SORL1 expression. We propose that the variation in SORL1 expression induction by BDNF is modulated by common genetic variants and can explain how genetic variation in this one locus can contribute to an individual's risk of developing SAD.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Young
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Boulanger-Weill
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Woodruff
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Floyd
authors.initials: F
authors.lastname: Buen
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Arra C
authors.initials: AC
authors.lastname: Revilla
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Herrera
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mason A
authors.initials: MA
authors.lastname: Israel
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shauna H
authors.initials: SH
authors.lastname: Yuan
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biostatistics, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Edland
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lgoldstein@ucsd.edu.
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012307:Risk Factors; D000685:Serum Amyloid A Protein / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D034741:RNA, Small Interfering; C102582:SORL1 protein, human; D000685:Serum Amyloid A Protein; C579455:BDNF protein, human