A Risk Factor for Alzheimer's Disease Regulates the Expression of a Novel Gene Associated with Intellectual Disability
Additional Funding Sources
The project described was supported by Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grants #P20GM103408 and P20GM109095.
Abstract
Alzheimer’s Disease (AD) is a progressive and fatal brain disorder characterized by memory loss and the destruction of thinking skills that currently affects over 5.1 million Americans. The biggest genetic risk factor for Alzheimer’s is a protein-encoding gene called ApoE4, but the mechanism by which ApoE4 contributes to AD is not well understood. A fragmented form of the ApoE4 protein has been shown to cause morphological changes and death in cells treated with the fragment. We hypothesized that the fragmented form of ApoE4 acts as a transcription factor by regulating genes related to apoptosis. We performed quantitative polymerase chain reaction to identify transcriptional changes in genes near a potential binding site of the ApoE4 fragment in the presence of the ApoE4 fragment. We found that the expression of a gene associated with intellectual disability, CXorf56, was repressed in microglial cells treated with the ApoE4 fragment. We then knocked down CXorf56 mRNA using small interfering RNA and imaged the cells with light microscopy. We observed changes in cell morphology following the knockdown of CXorf56. This study contributes to further understanding a novel pathophysiological role of ApoE4 and could potentially help explain how the inheritance of ApoE4 increases risk of AD.
A Risk Factor for Alzheimer's Disease Regulates the Expression of a Novel Gene Associated with Intellectual Disability
Alzheimer’s Disease (AD) is a progressive and fatal brain disorder characterized by memory loss and the destruction of thinking skills that currently affects over 5.1 million Americans. The biggest genetic risk factor for Alzheimer’s is a protein-encoding gene called ApoE4, but the mechanism by which ApoE4 contributes to AD is not well understood. A fragmented form of the ApoE4 protein has been shown to cause morphological changes and death in cells treated with the fragment. We hypothesized that the fragmented form of ApoE4 acts as a transcription factor by regulating genes related to apoptosis. We performed quantitative polymerase chain reaction to identify transcriptional changes in genes near a potential binding site of the ApoE4 fragment in the presence of the ApoE4 fragment. We found that the expression of a gene associated with intellectual disability, CXorf56, was repressed in microglial cells treated with the ApoE4 fragment. We then knocked down CXorf56 mRNA using small interfering RNA and imaged the cells with light microscopy. We observed changes in cell morphology following the knockdown of CXorf56. This study contributes to further understanding a novel pathophysiological role of ApoE4 and could potentially help explain how the inheritance of ApoE4 increases risk of AD.
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