Potential Therapeutic Implications of Gelsolin in Alzheimer's Disease

The presence of amyloid plaques and vascular amyloid deposits is one of the pathological features of Alzheimer's disease (AD). Amyloid plaques and vascular deposits mainly consist of amyloid-beta (A beta), which is a metabolic product of amyloid-beta protein precursor cleaved by beta- and gamma-secretase. Soluble A beta monomers readily aggregate into oligomers preceding the formation of insoluble fibrils, and A beta oligomers are more toxic than fibrils. Intensive therapeutic efforts have been attempted in the treatment of AD targeting A beta, including preventing A beta generation, inhibiting A beta aggregation, and promoting A beta clearance. The results show that amyloid plaque burden is reduced together with improved cognition performance in AD. Gelsolin, a multifunctional actin-binding protein, exists intracellularly as a cytoplasmic form and extracellularly as a secreted form in blood/cerebrospinal fluid. Gelsolin is suggested to be implicated in AD, based on the findings that some changes of gelsolin are correlated with disease progression rate in AD patients. Gelsolin binds A beta, inhibits its aggregation into fibrils, and protects cells from apoptosis induced by A beta. More importantly, administration or overexpression of gelsolin results in significant reduction of amyloid load and decrease of A beta level in AD transgenic mice. In this article, we review the most recent progress of gelsolin as a potential therapeutic strategy for treatment of AD, and discuss the possible mechanism involved in the clearance of amyloid plaques in AD.