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LIKE NSAIDS, some statin drugs--which are widely used as cholesterol-lowering agents--appear to show efficacy against Alzheimer's disease. Also like NSAIDs, statins may achieve this effect, at least in part, by influencing APP cleavage. The connection between statins and APP may lie along a pathway involving Rho, one of a family of molecules known as small guanosine triphosphate-binding proteins. These molecules, which are also referred to as small G proteins, controls many cellular functions, ranging from gene expression to cytoskeletal reorganization. Samuel E. Gandy, a neurologist at Thomas Jefferson University, Philadelphia, recently explored the effect of statins on the Rho pathway and APP processing in cultured neural cells [PLoS Medicine, 2, e18 (2005)]. In particular, Gandy and his collaborators were interested in ROCK1, a protein that Rho activates to carry out its tasks. Once activated, ROCK1 phosphorylates other proteins. This phosphorylation is mediated by molecules called isoprenoids. The researchers first confirmed that ROCK1 activation promotes "bad cleavage" of APP, thereby boosting A42 production. They then determined that the statin drugs atorvastatin (Lipitor) and simvastatin (Zocor) inhibit ROCK1 activity and tip the balance in favor of "good cleavage." The researchers believe that ROCK1 may exert its effect on APP cleavage via a-secretase. Gandy thinks that the interaction may be indirect, with ROCK1 phosphorylating an "accessory molecule" that then interacts with -secretase. Whatever the exact mechanism, the results "reveal an unsuspected pathway linking statins and amyloid metabolism," Gandy says. "This may help unravel statin action in Alzheimer's as well as point the way toward novel antiamyloid drugs," which could be designed to target ROCK1 directly. |
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