AUTHOR=Quan Wenqiang , Decker Yann , Luo Qinghua , Chemla Axel , Chang Hsin-Fang , Li Dong , Fassbender Klaus , Liu Yang 

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

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 18 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2024.1471005

DOI=10.3389/fncel.2024.1471005

ISSN=1662-5102

ABSTRACT=Activation of NLRP3-containing inflammasome, which is responsible for IL-1β 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. By cross-breeding human P301S tautransgenic mice and Nlrp3 knockout mice, and immunohistological and molecular biological analysis of brain tissues, we showed that deficiency of NLRP3: 1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, but 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. To investigate how NLRP3 regulates pericyte activation and survival, we cultured pericytes from the brains of Nlrp3 knockout and wild-type mice and analyzed the cells by confocal microscopy and flow cytometry after immunofluorescent staining. NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H2O2 increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner. Therefore, inhibition of NLRP3 may promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brains of tautransgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer's patients.