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

Introduction: 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.

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-1β and H₂O₂ at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ 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-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.

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.