Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells

Jessica E. Young; Jonathan Boulanger-Weill; Daniel A. Williams; Grace Woodruff; Floyd Buen; Arra C. Revilla; Cheryl Herrera; Mason A. Israel; Shauna H. Yuan; Steven D. Edland; Lawrence S.B. Goldstein

doi:10.1016/j.stem.2015.02.004

Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells

Jessica E. Young, Jonathan Boulanger-Weill, Daniel A. Williams, Grace Woodruff, Floyd Buen, Arra C. Revilla, Cheryl Herrera, Mason A. Israel, Shauna H. Yuan, Steven D. Edland, Lawrence S.B. Goldstein

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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.

Original language	English (US)
Pages (from-to)	373-385
Number of pages	13
Journal	Cell Stem Cell
Volume	16
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2015.02.004
State	Published - Apr 2 2015
Externally published	Yes

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© 2015 Elsevier Inc. All rights reserved.

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Young, J. E., Boulanger-Weill, J., Williams, D. A., Woodruff, G., Buen, F., Revilla, A. C., Herrera, C., Israel, M. A., Yuan, S. H., Edland, S. D., & Goldstein, L. S. B. (2015). Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell, 16(4), 373-385. https://doi.org/10.1016/j.stem.2015.02.004

Young, JE, Boulanger-Weill, J, Williams, DA, Woodruff, G, Buen, F, Revilla, AC, Herrera, C, Israel, MA, Yuan, SH, Edland, SD & Goldstein, LSB 2015, 'Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells', Cell Stem Cell, vol. 16, no. 4, pp. 373-385. https://doi.org/10.1016/j.stem.2015.02.004

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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.",

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Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells

Abstract

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