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-b (Ab). Endoproteolysis of the amyloid-b precursor protein (AbPP) by the b-secretase and the g-secretase generates Ab .A bPP can also be cleaved by the a-secretase within the Ab region, which releases a soluble fragment sAPPa and precludes the formation of Ab. Al has been reported to increase the level of Ab, promote Ab aggregation, and increase Ab neurotoxicity. In contrast, small G protein Rho and its effector, Rho-associated kinase (ROCK), are known to negatively regulate the amount of Ab. Inhibition of the RhoROCK pathway may underlie the ability of nonsteroidal antiinflammatory drugs and statins to reduce Ab production. Whether the Rho-ROCK pathway is involved in Al-induced elevation and aggregation of Ab 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 sAPPa 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 RhoROCK signaling pathway was involved in Al-induced effects in terms of the cell viability, the production of sAPPa, and the formation of amyloid fibril, which provides a novel mechanism underlying Al-induced neurotoxicity.