PEG-PEI/siROCK2 inhibits Aβ42-induced microglial inflammation via NLRP3/caspase 1 pathway.

Yunyun Liu, Han Zhang, Anping Peng, Xiaodong Cai, YuZhou Wang, Ke Tang, Xiuqin Wu, Yanran Liang, Limin Wang, Zhong Li

Neuroreport 2022 Jan 05

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There is an urgent need to develop therapeutic strategies to improve the treatment outcome of Alzheimer's disease. The treatment strategy of gene therapy mediated by nanocarrier systems brings new hope for the treatment of Alzheimer's disease. ROCK2 is involved in various pathological processes of Alzheimer's disease and may be a potential target for the treatment of Alzheimer's disease. Our previous study indicated that PEG-PEI/siROCK2 [polyethyleneglycol-polyethyleneimine deliver ROCK2-siRNA, (PPSR)] prevented Aβ42-induced neurotoxicity and showed a promising prospect for the treatment of Alzheimer's disease. However, whether PPSR has an effect on the microglial inflammation in Alzheimer's disease is still unclear. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay was used to detect the cytotoxicity of PEG-PEI and PPSR in primary microglial cells. Real-time PCR and western blotting were used to assess the expression of ROCK2 and nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/caspase 1 pathway in primary microglial cells. ELISA assay was used to measure the effect of PPSR on attenuating the lipopolysaccharide (LPS) + Aβ-induced increase in IL-1β. PEG-PEI concentration less than 20 μg/ml and the N/P (molar ratio of PEG-PEI amino/siRNA phosphate) ratio of PPSR less than 50 showed no significant cytotoxicity in primary microglia cells. PPSR could effectively inhibit the expression of ROCK2 in primary microglial cells. A further study revealed that PPSR attenuates the LPS+Aβ-induced increase in IL-1β without affecting cell viability. In addition, we found that PPSR suppressed the Aβ-induced NLRP3/caspase 1 pathway in primary microglial cells. PPSR inhibits Aβ42-induced microglial inflammation via NLRP3/caspase 1 pathway. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Citation

Yunyun Liu, Han Zhang, Anping Peng, Xiaodong Cai, YuZhou Wang, Ke Tang, Xiuqin Wu, Yanran Liang, Limin Wang, Zhong Li. PEG-PEI/siROCK2 inhibits Aβ42-induced microglial inflammation via NLRP3/caspase 1 pathway. Neuroreport. 2022 Jan 05;33(1):26-32