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  1. Fulltext REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease
    Meyer K, Feldman HM, Lu T, Drake D, Lim ET, Ling KH, et al.
    Cell Rep, 2019 01 29;26(5):1112-1127.e9.
    PMID: 30699343 DOI: 10.1016/j.celrep.2019.01.023
    The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.
    Matched MeSH terms: Apolipoproteins E/metabolism
  2. Fulltext Lack of association of apolipoprotein E (Apo E) polymorphism with the prevalence of metabolic syndrome: the National Heart, Lung and Blood Institute Family Heart Study
    Lai LY, Petrone AB, Pankow JS, Arnett DK, North KE, Ellison RC, et al.
    Diabetes Metab Res Rev, 2015 Sep;31(6):582-7.
    PMID: 25656378 DOI: 10.1002/dmrr.2638
    OBJECTIVE: Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidaemia, elevated blood pressure and insulin resistance, is a major public health concern in the United States. The effects of apolipoprotein E (Apo E) polymorphism on MetS are not well established.

    METHODS: We conducted a cross-sectional study consisting of 1551 participants from the National Heart, Lung and Blood Institute Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. MetS was defined according to the American Heart Association-National Heart, Lung and Blood Institute-International Diabetes Federation-World Health Organization harmonized criteria. We used generalized estimating equations to estimate adjusted odds ratios (ORs) for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis.

    RESULTS: Our study population had a mean age (standard deviation) of 56.5 (11.0) years, and 49.7% had MetS. There was no association between the Apo E genotypes and the MetS. The multivariable adjusted ORs (95% confidence interval) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62-1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47) and 1.87 (0.91-3.85) for the Ɛ3/Ɛ3, Ɛ2/Ɛ2, Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4 and Ɛ4/Ɛ4 genotypes, respectively. In a secondary analysis, Ɛ2/Ɛ3 genotype was associated with 41% lower prevalence odds of low high-density lipoprotein [multivariable adjusted ORs (95% confidence interval) = 0.59 (0.36-0.95)] compared with Ɛ3/Ɛ3 genotype.

    CONCLUSIONS: Our findings do not support an association between Apo E polymorphism and MetS in a multicentre population-based study of predominantly White US men and women.

    Matched MeSH terms: Apolipoproteins E/metabolism
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