The protective effect of rho-associated kinase inhibitor on aluminum-induced neurotoxicity in rat cortical neurons

Abstract

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-β (Aβ). Endoproteolysis of the amyloid-β precursor protein (AβPP) by the β-secretase and the g-secretase generates Aβ.AβPP can also be cleaved by the a-secretase within the Aβ region, which releases a soluble fragment sAPPa and precludes the formation of Aβ. Al has been reported to increase the level of Aβ, promote Aβ aggregation, and increase Aβ neurotoxicity. In contrast, small G protein Rho and its effector, Rho-associated kinase (ROCK), are known to negatively regulate the amount of Aβ. Inhibition of the Rho-ROCK pathway may underlie the ability of nonsteroidal anti-inflammatory drugs and statins to reduce Aβ production. Whether the Rho-ROCK pathway is involved in Al-induced elevation and aggregation of Aβ 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 Rho-ROCK 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. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.