Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene

Abstract

Alzheimer's disease (AD), the most common form of dementia, is a progressive, degenerative disorder of the central nervous system. The major hallmarks of AD include selective neuronal cell death and the presence of amyloid deposits and neurofibrillary tangles. Apolipoprotein E (ApoE) has also been shown to colocalize with these neuropathological lesions. Here is reviewed the role of ApoE in AD. The human ApoE gene has three alleles (epsilon2, epsilon3, epsilon4)-all products of the same gene. The epsilon3-allele accounts for the majority of the ApoE gene pool (approximately 70-80%), the epsilon4-allele accounts for 10-15% and the epsilon2 allele for 5-10%. Inheritance of the epsilon4-allele strongly increases the risk for developing AD at an earlier age. Functions of ApoE include cholesterol transport, neuronal repair, dendritic growth and anti-inflammatory activities. Putative pathological functions or "risk-factor activities" of ApoE-epsilon4 include its role in promoting amyloid accumulation, neurotoxicity, oxidative stress and neuro fibrillary tangles.ApoE mRNA is most abundant in the liver followed by the brain, where it is synthesized and secreted primarily by astrocytes. ApoE protein and mRNA are further detected in cortical and hippocampal neurons in humans. ApoE gene expression is induced by brain injury in some neurons and upregulated in astrocytes during aging. In AD, an increased ApoE mRNA was reported in the hippocampus. The risk for AD has been reported to correlate with transcriptional activity of the ApoE gene. Binding sites for putative transcriptional factors (TF), such as AP-1, AP-2 and NF-kappaB, are present in the ApoE promoter. The promoter also contains sites for the inflammatory response transcription factors IL-6 RE-BP, MED1, STAT1 and STAT2. A functional peroxisome-proliferator-activated receptor gamma (PPARgamma) has been detected in the ApoE/ApoCI intergenic region. ApoE mRNA levels were shown to be regulated by ciglitazone, a PPARgamma inducer. Certain statin drugs may also affect ApoE promoter activity. Two distal enhancers that specify ApoE gene expression in macrophages were identified. These results have implications for the regulation of ApoE gene expression, which plays an important role in the development of AD. The interaction of different transcription factors with the regulatory region of the ApoE gene is important to understand the neuroinflammatory process seen in AD.