Deficiency of NLRP3 protects cerebral pericytes and attenuates Alzheimer's pathology in tau-transgenic mice

被引:0
作者
Quan, Wenqiang [1 ,2 ]
Decker, Yann [2 ]
Luo, Qinghua [2 ,3 ]
Chemla, Axel [2 ]
Chang, Hsin-Fang [4 ,5 ]
Li, Dong [1 ]
Fassbender, Klaus [2 ]
Liu, Yang [1 ,2 ,5 ]
机构
[1] Tongji Univ, Tongji Hosp, Dept Clin Lab, Med Sch, Shanghai, Peoples R China
[2] Saarland Univ, Dept Neurol, Homburg, Germany
[3] Nanchang Univ, Dept Neurol, Affiliated Hosp 2, Nanchang, Peoples R China
[4] Saarland Univ, Ctr Integrat Physiol & Mol Med CIPMM, Cellular Neurophysiol, Homburg, Germany
[5] Saarland Univ, Ctr Gender Spec Biol & Med CGBM, Homburg, Germany
基金
中国国家自然科学基金;
关键词
Alzheimer's disease; cerebrovascular disorders; NLRP3; pericyte; tau; DISEASE-RELATED SYMPTOMS; ACTIVATION; BRAIN; CELLS; PATHWAY; EXPRESSION; APOPTOSIS; BETA;
D O I
10.3389/fncel.2024.1471005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Introduction Activation of NLRP3-containing inflammasome, which is responsible for IL-1 beta maturation, has been shown to contribute to Alzheimer's disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown.Methods NLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and Nlrp3 knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of Nlrp3 knockout and wild-type mice were cultured, treated with IL-1 beta and H2O2 at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFR beta antibody.Results Deficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated Osteopontin gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1 beta or H2O2 increased the expression of PDGFR beta in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner.Discussion Inhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer's patients.
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页数:12
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