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Dementia in a dish

Lawrence Goldstein and colleagues report the generation of induced pluripotent stem cell (iPSC) lines and their derived neurons from patients with sporadic late-onset Alzheimer's disease (LOAD), the most common form of the disease (Cell Stem Cell 16, 373–385, 2015). Although hundreds of genetic variants have been reported to associate with sporadic LOAD, the genetic heterogeneity of the disease and low penetrance of risk variants make it extremely difficult to determine how risk variants contribute to pathogenicity. Goldstein and colleagues focused on a single candidate risk gene, SORL1, which encodes an endocytic trafficking protein involved in regulation of APP processing. They observed no difference in SORL1 expression levels between iPSC-derived neurons from patients with probable sporadic LOAD and those from patients without apparent dementia. However, only neurons carrying a known protective haplotype of SORL1 were sensitive to a brain-derived neurotrophic factor (BDNF)-induced increase in SORL1 expression. Analysis of available case-control data supported the finding that the protective haplotype is dominant. The authors found that BDNF-induced SORL1 expression was correlated with a decrease in production of Aβ peptides and that this decrease required SORL1. These results point to a potential mechanism underlying the association between SORL1 variants and LOAD.

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LaFlamme, B. Dementia in a dish. Nat Genet 47, 429 (2015). https://doi.org/10.1038/ng.3294

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