Alzheimer's disease (AD) is characterized by excessive accumulation of beta amyloid (A beta), as a consequence of alternate processing of APR, and A beta-induced plaque and associated neuroinflammation promote AD pathology. Documentation of hypercholesterolemia as a risk factor for AD and reduced prevalence of AD among patients using statins and reduced load of A beta in AD mice treated with statins support of a role of metabolites (cholesterol and isoprenoids) of the mevalonate pathway in the pathobiology of AD. Studies from our laboratory have also reported that in addition to regulation of cholesterol levels statins also have anti-inflammatory properties. Based on the anti-inflammatory properties of statins, this drug is now being tested as a possible therapeutic agent for neuroinflammatory/neurodegenerative disease, however, very little is known about the mechanism of action of these drugs in neuroinflammatory diseases. Therefore, the proposed studies are designed to understand the mechanism of action of metabolites of the mevalonate pathway in multitasking activities of statins in the A beta mediated oligodendrocyte toxicity and astrocyte/microglia induced inflammatory disease by using a cell culture model of AD (Specific Aims 1 and 2) and their efficacy in lowering cholesterol on the burden of A beta accumulation and inflammatory disease with an animal model of AD (TgCRNDS) (Specific Aim 3). Understanding anti-amyloidogenic and immunomodulatory properties of statins should help establish their utilitiy as a novel noninvasive prophylactic therapy for reducing amyloid burden and inflammation simultaneously in the management of AD.
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