Anti-amyloidogenic, anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer's disease

Fibrillar amyloid beta-protein (A beta) is a major component of amyloid plaques in the brains of individuals with Alzheimer's disease (AD) and of adults with Down syndrome (DS). Gelsolin, a cytoskeletal protein, is present both intracellularly (cytoplasmic form) and extracellularly (secretory form in biological fluids). These two forms of gelsolin differ from each other in length and in cysteinyl thiol groups. Previous studies from our and other groups have identified the anti-amyloidogenic role of gelsolin in AD. Our studies showed that both plasma and cytosolic gelsolin bind to A beta, and that gelsolin inhibits the fibrillization of A beta and solubilizes preformed fibrils of A beta. Other studies have shown that peripheral administration of plasma gelsolin or transgene expression of plasma gelsolin can reduce amyloid load in the transgenic mouse model of AD. Our recent studies showed that gelsolin expression increases in cells in response to oxidative stress. Oxidative damage is considered a major feature in the pathophysiology of AD. A beta not only can induce oxidative stress, but also its generation is increased as a result of oxidative stress. In this article, we review evidence of gelsolin as an anti-amyloidogenic agent that can reduce amyloid load by acting as an inhibitor of A beta fibrillization, and as an antioxidant and anti-apoptotic protein.