Cholesterol Metabolism in Alzheimer's Disease and Other Age-Related Conditions

Cholesterol metabolism is interesting in that humans (a) do not break down cholesterol to any great degree, and (b) cholesterol is only created in a limited number of locations in the body. Thus intricate mechanisms shuffle cholesterol from place to place via the circulatory system. LDL particles carry cholesterol from the liver to the body, APOE aids in cellular update of cholesterol, ABCA1 enables cells to hand off cholesterol to HDL particles, and those HDL particles carry cholesterol to the liver. That high level sketch expands out into a much more complex picture if one looks more closely, but it gives a sense of the way in which cholesterol transport functions. These systems tend to break down in the environments of too much cholesterol, too much oxidation of cholesterol, and so forth. That gives rise to localized excesses of cholesterol and a range of conditions that include, most prominently, atherosclerosis.

Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer's disease, but rather than affecting the body as a whole, the effects are localized in the brain. When cholesterol rises, due to insulin resistance or other factors, the body starts a process known as reverse cholestrol transport, during which specific molecules carry excess cholesterol to the liver to be excreted.

Apolipoprotein E (APOE) is one of the proteins involved in reverse cholesterol transport. APOE is also the strongest risk factor gene for Alzheimer's disease and related dementia, and an independent risk factor for Type 2 diabetes and cardiovascular disease. Similarly, reduced activity of another cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), correlates with increased risk of cardiovascular disease, Type 2 diabetes, and Alzheimer's disease. "While most people are aware of so-called 'good cholesterol (HDL),' and 'bad cholesterol (LDL),' associated with risk of heart attack and stroke, these broad concepts are also applicable to a healthy brain. Moving cholesterol to where it is needed in the body has positive effects on many physiological processes and can help clear misfolded proteins that accumulate in the brain."

Increasing the activity of ABCA1 is expected to positively influence insulin signaling and reduce inflammation in the brain, making it a potential therapy for both Type 2 diabetes and Alzheimer's disease. In this study, the research team designed a way to identify small molecules that improve the function of ABCA1 in the body while avoiding unwanted effects to the liver. The researchers honed in on a specific small molecule, CL2-57, due to its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.


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