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2022, Vol. 26 ›› Issue (2): 232-238Fasudil inhibits neuronal apoptosis via regulating mitochondrial dynamics in APP/PS1 miceWei Wenyue1, 2, 3, Wang Yuyin2, 3, Guo Minfang3, Zhang Jing2, 3, Gu Qingfang3, Song Lijuan1, 2, Chai Zhi1, 2, 3, Yu Jiezhong1, 3, 4, Ma Cungen1, 2, 3
Abstract: BACKGROUND: The pathogenesis of Alzheimer’s disease is closely related to abnormal mitochondrial dynamics. Our previous research demonstrated that Fasudil has neuroprotective effect. However, it is needed to explore whether Fasudil has beneficial effect on regulating mitochondiral dynamics. OBJECTIVE: To investigate the effect and mechanism of ROCK inhibitor on cognitive function and neuronal apoptosis in Alzheimer’s disease mice. METHODS: Amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were randomly divided into the Fasudil group (25 mg/kg/d) and normal saline group (equivalent volume normal saline), and wild-type C57BL/6 mice at the same age and gender served as normal controls (same volume normal saline). Administration in each group was given via intraperitoneal injection once daily for 2 months. Spatial cognition of mice was detected by Morris water maze test and Y maze test. Nissl staining was used to observe and analyze the number and morphology of neurons. TUNEL staining was applied to observe neuronal apoptosis. The protein levels of NeuN, Bax, Bcl-2, Cleaved Caspase-3, dynamin-related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), optic atrophic protein 1 (OPA1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2) in hippocampus tissue were determined by western blot test. The expression of NeuN and DRP1 was detected by immunofluorescence staining. RESULTS AND CONCLUSION: Fasudil ameliorated cognitive impairment and improved loss of learning, memory and exploration function in APP/PS1 mice. Compared with the normal control group, the number of survived neurons was decreased, the apoptotic rate of neurons was increased, the expression of Bax and Cleaved Caspase-3 was increased, but the expression of NeuN and Bcl-2 was decreased in APP/PS1 mice. These changes were all strongly reversed by a 2-month treatment of Fasudil. Fasudil markedly down-regulated the expression of DRP1 and FIS1, but remarkably up-regulated the expression of OPA1, Mfn1, and Mfn2. These findings indicate that Fasudil significantly improves the spatial cognitive function in APP/PS1 mice, which may be related to restoring the mitochondrial fission and fusion imbalance so as to inhibit neuronal apoptosis. Key words:Alzheimer’s disease, Fasudil, APP/PS1 mice, cognitive disorder, apoptosis, mitochondrial dynamics, mitochondria fission and fusion, neuroprotection |