Title:Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice
Volume: 16
Issue: 2
Author(s): Jie-Zhong Yu, Yan-Hua Li, Chun-Yun Liu, Qing Wang, Qing-Fang Gu, Hui-Qing Wang, Guang-Xian Zhang, Bao-Guo Xiao and Cun-Gen Ma
Affiliation:
Keywords:
Alzheimer's disease, Rho kinase, Fasudil, APP/PS1 Tg mice.
Abstract: Introduction: Therapeutic strategies targeting Alzheimer’s disease-related molecule β-
amyloid (Aβ), Tau protein and β-site amyloid precursor protein cleaving enzyme (BACE) have been recently
explored. However, the treatment effect for single target is not ideal. Based on multiaspect roles
of Rho kinase inhibitor Fasudil on neuroprotection, neurorepair and immunomodulation, we observed
therapeutic potential of Fasudil and explored possible mechanisms in amyloid precursor protein/
presenilin-1 transgenic (APP/PS1 Tg) mice, an animal model of Alzheimer’s disease.
Methods: APP/PS1 Tg mice were treated with Fasudil (25 mg/kg/day) for 2 months by intraperitoneal
injection. Mouse behavior tests were recorded every day. The expression of Aβ deposition, Tau protein
phosphorylation, BACE and postsynaptic density 95 (PSD-95) in hippocampus was assayed. The levels
in the brain of Toll-like receptors (TLRs)-nuclear factor kappa B/p65（NF-κB/p65)- myeloid differentiation
primary response gene 88 (MyD88) inflammatory cytokine axis were measured.
Results: Fasudil treatment ameliorated learning and memory deficits, accompanied by reduced Aβ
deposition, Tau protein phosphorylation, and BACE expression, as well as increased PSD-95 expression
in hippocampus. Fasudil intervention also inhibited TLR-2/4, p-NF-κB/p65, MyD88, interleukin-1beta,
interleukin-6 and tumor necrosis factor-α for TLRs-NF-κB-MyD88 inflammatory cytokine axis and the
induction of interleukin-10.
Conclusion: Fasudil exhibited multitarget therapeutic effect in APP/PS1 Tg mice. The study provides
preclinical evidence that Fasudil treatment ameliorated memory deficits in APP/PS1 Tg mice, accompanied
by the reduction of Aβ deposition and Tau protein phosphorylation, the decrease of BACE and
the increase of PSD-95, as well as inhibition of TLRs-NF-κB-MyD88 inflammatory cytokine axis.
However, these results still need to be repeated and confirmed before clinical application.
