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

Metab Brain Dis. 2019 Dec;34(6):1787-1801. doi: 10.1007/s11011-019-00487-0. Epub 2019 Sep 3.

Abstract

Alzheimer's disease (AD), a chronic, progressive, neurodegenerative disorder, is the most common type of dementia. Beta amyloid (Aβ) 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 Aβ1-42 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 Aβ burden (46.65%), Tau phosphorylation (96.84%), and ROCK-II expression. In addition, fasudil reversed Aβ1-42-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 Aβ1-42. These results suggest that inhibition of Rho kinase by fasudil reverses Aβ1-42-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.

Keywords: Alzheimer’s disease; Apoptosis; Aβ1–42; Fasudil; JNK; Neurons; Rho kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Amyloid beta-Peptides
  • Animals
  • Apoptosis / drug effects*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • MAP Kinase Kinase 4 / metabolism*
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mice
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptide Fragments
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • rho-Associated Kinases / antagonists & inhibitors
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • amyloid beta-protein (1-42)
  • tau Proteins
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase 4
  • fasudil