Cholesterol and Alzheimer's Disease: The Molecules, the Targets
The involvement of alterations in the metabolism of cholesterol in Alzheimer's disease (AD) is nowadays undisputable. The first link was established 15 years ago with the discovery of the allele 4 of the cholesterol transport protein apoE as a risk factor to suffer the late onset forms of the disease. Since then, many other cholesterol-related molecules have been associated to AD. These participate in practically all aspects of cholesterol metabolism including synthesis, degradation, uptake, transport or intracellular distribution. Although in most of the cases we ignore how cholesterol alterations predispose to disease, i.e. because of peripheral (circulatory) or central (brain) defects, several of these molecules are considered potential targets for AD prevention and treatment. Circulatory and brain cholesterol play key roles in the generation of the amyloid peptide in peripheral cells and in neurons as well as in the entry of the peptide from the circulation into the brain and in its excretion from the brain into the circulation. Therefore, the strategy of modulating cholesterol levels appears more than logical. However, the usefulness for the disease of any cholesterol modifying drugs needs to be carefully assessed, as cellular cholesterol is most essential for crucial cell activities and any long-term perturbation of its levels or distribution within cells may lead to most undesirable consequences. Hence, despite many promising aspects cholesterol modulation-based strategies require further investigation, at the basic and applied level.