ApoE4 Linked to Various Diseases by Transcription Factor Activity

The lipid-binding protein apolipoprotein E4 (ApoE4) has been found to act as a transcription factor with binding sites on more than 1,700 genes, many of which are linked to diverse disease syndromes such as Alzheimer's disease (AD), atherosclerotic cardiovascular disease, Lewy body dementia, and inflammation.

A major unanswered question in biology and medicine has been the mechanism by which the lipid-binding protein ApoE4—the product of the apolipoprotein E epsilon4 allele—operates in the various disease states to which it has been linked.

To clarify this issue, investigators at the Buck Institute for Research on Aging (Los Angeles, CA, USA) used chromatin immunoprecipitation and high-throughput DNA sequencing to evaluate gene apolipoprotein E activity in a combination of neural cell lines, skin fibroblasts from AD patients, and ApoE targeted mouse brains.

The investigators reported in the January 20, 2016, online edition of the Journal of Neuroscience that ApoE4 underwent nuclear translocation, bound double-stranded DNA with high affinity, and functioned as a transcription factor. They found that ApoE4's binding sites included 1,700 promoter regions that comprised genes associated with neurotrophins, programmed cell death, synaptic function, sirtuins and aging, and insulin resistance—all processes that have been implicated in the development of Alzheimer's disease.

Of particular interest was the inhibitory effect of ApoE4 on the enzyme sirtuin 1 (SIRT1, silent mating type information regulation 2 homolog 1). This enzyme is a histone deacetylase involved in numerous critical cell processes including DNA repair and apoptosis, which had been linked to healthy metabolism throughout the body, including organs like the pancreas and liver.

"Our group hopes this work will lead to a new type of screen for Alzheimer's prevention and treatment," said senior author Dr. Rammohan Rao, an associate research professor at the Buck Institute for Research on Aging. "We are also designing and engineering novel drug candidates that target not one, but several of the ApoE4 mediated pathways simultaneously. Ultimately we want to develop a drug that can be given to ApoE4 carriers that would prevent the development of Alzheimer's disease, and these results provide a mechanism and screen to do that."

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Buck Institute for Research on Aging