The Protective Effect of Rho-Associated Kinase Inhibitor on Aluminum-Induced Neurotoxicity in Rat Cortical Neurons

Aluminum (Al) is a neurotoxicant and is implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). In AD brains, one of the pathological hallmarks is the extracellular deposition of senile plaques, which are mainly composed of aggregated amyloid-beta (A beta). Endoproteolysis of the amyloid-beta precursor protein (A beta PP) by the beta-secretase and the gamma-secretase generates A beta. A beta PP can also be cleaved by the alpha-secretase within the A beta region, which releases a soluble fragment sAPP alpha and precludes the formation of A beta. Al has been reported to increase the level of A beta, promote A beta aggregation, and increase A beta neurotoxicity. In contrast, small G protein Rho and its effector, Rho-associated kinase (ROCK), are known to negatively regulate the amount of A beta. Inhibition of the Rho-ROCK pathway may underlie the ability of nonsteroidal anti-inflammatory drugs and statins to reduce A beta production. Whether the Rho-ROCK pathway is involved in Al-induced elevation and aggregation of A beta is unknown. In the present study, cultured rat cortical neurons were treated with Al(malt)(3) in the absence or presence of ROCK inhibitor Y-27632. After the treatment of Al(malt)(3), the cell viability and the level of sAPP alpha were reduced, whereas the amyloid fibrils in the conditioned media were increased. Treatment with Y-27632 prevented these adverse effects of Al(malt)(3) and thus maintained neuronal survival. These results reveal that the activation of the Rho-ROCK signaling pathway was involved in Al-induced effects in terms of the cell viability, the production of sAPP alpha, and the formation of amyloid fibril, which provides a novel mechanism underlying Al-induced neurotoxicity.