Project 171063

The discovery that possesion of apolipoprotein E4 is the only risk factor that is consistently found associated with the most common, non-familial form of Alzheimer's disease (AD) led us to focus on the role of cholesterol in the pathogenesis of AD. Accumulating epidemiological and biological evidence suggests a link between cholesterol levels and the development of AD, and the potential therapeutic effectiveness of statins for AD. The effectiveness of lowering cholesterol levels in decreasing the risk for AD is not absolute and other lines of evidence show controversial results. We have have found that amyloid-beta, the substance that accumulates in the brain of AD patients, increases cholesterol inside nerve cells. Our hypothesis is that, due to cholesterol accumulation, the compartments inside the cells do not function properly, which in turn leads to the death of the nerve cells. We propose to study the details of cholesterol accumulation inside nerve cells and the impact of the type of apoE (apoE2, apoE3 or apoE4)in preventing cholesterol accumulation. Therapeutic strategies aimed to reduce cholesterol levels are being tested in humans for the treatment of AD, which poses the urgency to fully understand cholesterol homeostasis in neurons. Our studies will help us understand better the reasons behind this devastating disease and will contribute to the final evaluation about the effectiveness and mechanisms of treatment with the cholesterol synthesis inhibitors.

studying the role of cholesterol homeostasis and apoE isoforms in amyloid-beta induced neurotoxicity