Cytoplasmic gelsolin increases mitochondrial activity and reduces Aβ burden in a mouse model of Alzheimer's disease

Accumulation of amyloid-beta (A beta) peptides is thought to be a critical event in the pathology of Alzheimer's disease (AD), because they induce multiple neurotoxic effects, including mitochondrial dysfunction and apoptotic cell death. Therefore the reduction of A beta is considered a primary therapeutic target. Gelsolin, an A beta binding protein, has been shown to inhibit apoptosis, although the underlying mechanism is unclear. To clarify these effects, we manipulated cytoplasmic gelsolin levels through viral-directed overexpression in the brain of APP/Ps1 transgenic mice. We observed that gelsolin reduces brain A beta burden in the APP/Ps1 mice, possibly by enhancing A beta clearance via megalin. The reduction in brain A beta levels was accompanied by an inhibition of nitric oxide production and cell death, not only in the choroid plexus but also in the cerebral cortex. Notably, overexpressed gelsolin restored the impaired mitochondrial activity in the APP/Ps1 mice, resulting in the increase of cytochrome c oxidase activity. By contrast, RNA interference to block gelsolin expression, confirmed that cytoplasmic gelsolin acts as a modulator of brain A beta levels and its neurotoxic effects. We conclude that gelsolin might prevent brain amyloidosis and A beta-induced apoptotic mitochondrial changes. These findings make cytoplasmic gelsolin a potential therapeutic strategy in AD. (C) 2009 Elsevier Inc. All rights reserved.