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.
Bibliographical noteFunding Information:
J.E.Y. is funded by postdoctoral fellowships from the California Institute of Regenerative Medicine, the A.P. Gianinni Foundation for Medical Research, and the BrightFocus Foundation. L.S.B.G. is funded by the California Institute of Regenerative Medicine (CIRM Tools and Technologies II, RT2-01927), CIRM Basic Biology V, (RR5-07011), and the NIH (NIH-NIA 2P50AG005131-31). We thank the donors of fibroblast samples from the UCSD Shiley-Marcos ADRC.
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