Changes in Apolipoprotein E Expression in Response to Dietary and Pharmacological Modulation of Cholesterol

Abstract

Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer's disease (AD) in an isoform-dependent manner, such that the presence of the apoE epsilon4 allele increases the risk of AD while the presence of the apoE epsilon2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the "risk factor" activity of AD, its ability to bind amyloid beta peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Abeta accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer's amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

“…In rodents, elevated apoE levels correlate with impaired cognitive function (Kadish et al 2009). Increased apoE expression resulting from high dietary cholesterol in humans is also associated with an increased incidence of AD (Petanceska et al 2003). Nonhuman primates show an age-related decline in performance on tasks associated with PFC and hippocampal Fig.…”

Dietary Cholesterol and Estrogen Administration Elevate Brain Apolipoprotein E in Mice by Different Mechanisms

“…Role of disrupted cholesterol metabolism in a transgenic mouse model of AD has been studied, which shows that the dietinduced chronic changes in plasma cholesterol also increase apoE content in the liver and the brain 42 . These findings have been further corroborated by the increased secretion of apoE by glial cells following cholesterol loading, and decreased apoE, following treatments with statins 42 . These data corroborate the findings in the present study that dietary cholesterol up-regulates brain apoE by transcriptional mechanism.…”

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease

“…Increased generation and secretion of A ␤ leads to the formation of oligomeric and aggregated A ␤ . Chronic increases in serum total cholesterol also increase apoE mRNA levels in brain and increase glial cell and secreted apoE levels (95). Studies in animal models have shown that diet-induced hypercholesterolemia increases A ␤ and apoE concentrations in temporal and frontal cortices, but not in cerebellum, and that these regional increases parallel the amyloid pathology observed in the AD brain (96).…”