The Rho kinase inhibitor fasudil attenuates Aβ1-42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons

Alzheimer's disease (AD), a chronic, progressive, neurodegenerative disorder, is the most common type of dementia. Beta amyloid (A beta) peptide aggregation and phosphorylated tau protein accumulation are considered as one of the causes for AD. Our previous studies have demonstrated the neuroprotective effect of the Rho kinase inhibitor fasudil, but the mechanism remains elucidated. In the present study, we examined the effects of fasudil on A beta (1-42) aggregation and apoptosis and identified the intracellular signaling pathways involved in these actions in primary cultures of mouse hippocampal neurons. The results showed that fasudil increased neurite outgrowth (52.84%), decreased A beta burden (46.65%), Tau phosphorylation (96.84%), and ROCK-II expression. In addition, fasudil reversed A beta (1-42)-induced decreased expression of Bcl-2 and increases in caspase-3, cleaved-PARP, phospho-JNK(Thr183/Tyr185), and phospho-ASK1(Ser966). Further, fasudil decreased mitochondrial membrane potential and intracellular calcium overload in the neurons treated with A beta (1-42). These results suggest that inhibition of Rho kinase by fasudil reverses A beta (1-42)-induced neuronal apoptosis via the ASK1/JNK signal pathway, calcium ions, and mitochondrial membrane potential. Fasudil could be a drug of choice for treatment of Alzheimer's disease.