ApoE4 Linked to Various Diseases by Transcription Factor Activity

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."

Related Links:
Buck Institute for Research on Aging