[Fasudil improves cognitive function in APP/PS1 transgenic mice by promoting mitophagy and inhibiting NLRP3...

Objective To explore the mechanism of fasudil improving cognitive dysfunction in amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice based on mitophagy and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway. Methods APP/PS1 mice were divided into model group and treatment group, and C57BL/6 mice were used as control group. The treatment group was given intraperitoneal injection of Fasudil (25 mg/kg) once daily for 2 months, while the control group and the model group were injected with the same volume of normal saline. The behavior of mice was detected by water maze and Y maze test; Nissl staining and neuron-specific nuclear antigen (NeuN) immunofluorescence histochemical staining were used to evaluate the number and morphology of neurons. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining was used to detect neuronal apoptosis; The expression of P62 and NLRP3 was detected by immunofluorescence histochemical staining; Real time fluorescence quantitative PCR was used to detect the mRNA expression levels of phosphatase and tensin homolog deleted on chromosome ten (PTEN) -induced putative kinase 1 (PINK1), Parkin and NLRP3; Western blot analysis was used to detect the expression of PINK1, Parkin, P62, microtubule-associated protein 1 light chain 3 (LC3), NLRP3, adapter protein apoptosis-associated speck-like protein (ASC) and interleukin-18 (IL-18). Results The results of the water maze and Y maze showed that the cognitive behavior of mice in treatment group was significantly improved, and their spatial memory and exploration abilities were significantly enhanced; The results of Nissl staining and NeuN immunofluorescence histochemical staining showed that the number of neurons and Nissl bodies were lower in the model group than that in the control group, while the morphology and number of neurons were improved after fasudil treatment. The results of TUNEL staining also showed that the number of apoptotic cells in the brain tissue of APP/PS1 mice were decreased after fasudil treatment; Compared with the control group, the expression of PINK1 and Parkin in the model group decreased, while the expression of P62, LC3, NLRP3, ASC and IL-18 increased. After treatment with fasudil, the expression of PINK1, Parkin, and LC3 increased, while the expression of P62, NLRP3, ASC, and IL-18 decreased. Conclusions Fasudil can improve the cognitive function and neuronal damage in APP/PS1 mice, and its mechanism may be related to promoting mitochondrial autophagy and inhibiting the activation of NLRP3 inflammasomes.