As I had mentioned in class, there has been an establishment of cholesterol as a risk factor in the pathogenesis of Alzheimer’s disease (AD). This is a major focus of current research for AD. I came across a review article from PubMed titled, Alzheimer’s disease: the cholesterol connection, and found that in the past few years, this link has been supported through genetic, epidemiological and biochemical data. The review was from Harvard Medical School’s Neurobiology of Disease Laboratory and Genetics and Aging Research Unit.
In all forms of Alzheimer’s disease (AD) there is an abnormal accumulation of the beta-amyloid protein in specific brain regions, which is regulation by cholesterol. It was found that elevated levels of cholesterol increase the beta-amyloid protein in cellular and most animal models of AD, and that drugs that inhibit cholesterol synthesis lower the beta-amyloid levels. Recent studies have shown that the total amount and distribution of cholesterol within neurons impact the beta-amyloid biogenesis. I mentioned in class the role of the apolipoprotien E gene, the identification of a variant of this gene as a major genetic risk factor for AD is consistent with a role for cholesterol in the pathogenesis of AD.
The review describes its recent findings concerning the molecular mechanisms underlying the cholesterol-AD connection. Drugs that lower cholesterol levels are currently being considered and tested as potential therapies for the treatment of AD. Statins, which are relatively safe and have been used for a long time against high cholesterol levels, are now being directly tested in clinical trials for efficacy against AD. Some of the potentially beneficial effects of statins might also represent improved cardiovascular health, resulting in a reduction in ischemic events that are also considered risk factors for AD. An effective therapy for patients whose cognitive function does not benefit from statin treatment may ultimately consist of a combination of lipid regulating products, perhaps in combination with statins. Alternative products for cholesterol management so far include extended-release niacin, cholesterol absorption inhibitiors, ACAT inhibitors and cholesteryl ester transfer protein (CETP) inhibitors. Results from in vitro studies suggest that ACAT inhibitors are good candidates for regulating beta-amyloid biogenesis, but more research is needed to understand the exact molecular mechanisms underlying the AD-cholesterol connection. Also, it is necessary to gain an in-depth understanding of brain cholesterol metabolism. With new technology that is developing, we may be able clarify how plasma and brain cholesterol contribute to AD.
Full PDF text found at EBSCHOhost:
Title: Alzheimer's disease: the cholesterol connection.
Author: Puglielli, Luigi; Tanzi, Rudolph E.; Kovacs, Dora M.;http://web.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=2&hid=106&sid=86523406-21ed-4ee6-8f03-87d50b8af3df%40sessionmgr110
The idea that high cholesterol levels could be linked to neurodegenerative diseases is really interesting and could hint at a reason for the increasing prevalence of neurodegenerative diseases. Earlier in the semester we were talking about the growing problem of obesity in America; could it be possible that increased cholesterol levels derived from a poor diet and sedentary lifestyle could lead to an increased risk of neurovascular issues later on in life? Then the obvious question is whether the loss of weight and lowering of cholesterol levels would eliminate the risk, or would permanent damage be done from the obesity?
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