期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 3, 页码 685-700出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3562-15.2016
关键词
activity-dependent neuroprotective protein; Alzheimer's disease; amyloid precursor protein; apolipoprotein E; MAP kinase-activating death domain; sirtuin
资金
- National Institutes of Health [AG034427]
- Joseph Drown Foundation
- Buck-Impact Circle Funds
- Marin Community Foundation
- Stephen D. Bechtel Jr. Foundation
- John and Bonnie Strauss Foundation
A major unanswered question in biology and medicine is the mechanism by which the product of the apolipoprotein E epsilon 4 allele, the lipid-binding protein apolipoprotein E4 (ApoE4), plays a pivotal role in processes as disparate as Alzheimer's disease (AD; in which it is the single most important genetic risk factor), atherosclerotic cardiovascular disease, Lewy body dementia, hominid evolution, and inflammation. Using a combination of neural cell lines, skin fibroblasts from AD patients, and ApoE targeted replacement mouse brains, we show in the present report that ApoE4 undergoes nuclear translocation, binds double-stranded DNA with high affinity (low nanomolar), and functions as a transcription factor. Using chromatin immunoprecipitation and high-throughput DNA sequencing, our results indicate that the ApoE4 DNA binding sites include similar to 1700 gene promoter regions. The genes associated with these promoters provide new insight into the mechanism by which AD risk is conferred by ApoE4, because they include genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, aging, and insulin resistance, all processes that have been implicated in AD pathogenesis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据