Fasudil reduces       β   -amyloid levels and neuronal apoptosis in APP/PS1 transgenic mice via inhibition of the Nogo-A/NgR/RhoA signaling axis

² Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, P. R. China

³ Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, 030001, P. R. China

⁴ Department of Neurology, Datong Fifth People's Hospital, Datong, 037009, P. R. China

^*Correspondence: sxdtyjz2020@163.com (Jie-Zhong Yu); macungen2001@163.com (Cun-Gen Ma)

J. Integr. Neurosci. 2020, 19(4), 651–662; https://doi.org/10.31083/j.jin.2020.04.243

Submitted: 13 August 2020 | Revised: 6 October 2020 | Accepted: 20 October 2020 | Published: 30 December 2020

This is an open access article under the CC BY 4.0 license ( https://creativecommons.org/licenses/by/4.0/).

Abstract

Recent studies have shown that Nogo-A and the Nogo-A receptor affect $\beta$ -amyloid metabolism and the downstream Rho GTP enzyme signaling pathway, which may affect the levels of $\beta$ -amyloid and tau. Nogo-A may play a key role in the pathogenesis of Alzheimer’s disease. However, the underlying molecular mechanisms of Fasudil treatment in Alzheimer’s disease are not yet clear. Our results have found that Fasudil treatment for two months substantially ameliorated behavioral deficits, diminished $\beta$ -amyloid plaque and tau protein pathology, and alleviated neuronal apoptosis in APP/PS1 transgenic mice. More importantly, two well-established markers for synaptic function, growth-associated protein 43 and synaptophysin, were upregulated after Fasudil treatment. Finally, the levels of Nogo-A, Nogo-A receptor complex NgR/p75NTR/LINGO-1 and the downstream Rho/Rho kinase signaling pathway were significantly reduced. These findings suggest that Fasudil exerts its neuroprotective function in Alzheimer’s disease by inhibiting the Nogo-A/NgR1/RhoA signaling pathway.

Keywords

Fasudil

Alzheimer's disease

\beta

-amyloid

apoptosis

Nogo-A/NgR/RhoA

hyper-phosphorylated tau (p-tau)

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Fig. 1.

Fasudil improves spatial learning of APP/PS1 Tg mice. Eight-month-old APP/PS1 Tg mice were injected with saline (n = 8) or Fasudil (n = 8) for two months. (a) Typical diagram of the Morris water maze test and the corresponding parameters. (b) Latency to target and mean distance to target for five consecutive daily tests. (c) On the sixth day, latency to target, mean distance to target, latency to first entrance to the SW zone were recorded in a retention test session, representing the time spent and distance traveled by animals from the starting point onto the platform or to the SW zone. (d) Typical diagram of the Y maze tests. (e) The percentage of time spent in the novel arm and the spontaneous alternation rate of each group in Y maze tests. Quantitative results for several parameters are mean $\pm{}$ SEM of the eight mice in each group. ${}^{*}$ P $<$ 0.05, ${}^{**}$ P $<$ 0.01, ${}^{***}$ P $<$ 0.001.

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