MnO nanozyme-based anti-inflammatory therapy modulates microglial phenotype by downregulating TLR4/NOX2 expression and further alleviates Alzheimer's disease pathology.

Evidence shows that neuroinflammation mediated by microglial activation plays an important role in Alzheimer's disease (AD) pathogenesis. However, the relationship between microglial phenotype and fibrillar β-amyloid (fAβ) pathology in anti-inflammatory treatment of AD remains unclear. We designed a water-soluble MnO nanozymes and demonstrated its ability to reverse lipopolysaccharide (LPS)-induced microglial transition from M1 to M2 phenotype by clearing reactive oxygen species (ROS). In 5×FAD transgenic mice, intranasal (IN) instillation of MnO nanozymes initially promoted M2 microglial polarization and significantly reduced neuroinflammation after 4 weeks of treatment. After 8 weeks of continuous treatment, they further alleviate fAβ pathology and improved learning and memory deficits in 5×FAD mice. The excellent anti-inflammatory effect of MnO nanozymes is achieved by inhibiting the Toll-like receptor 4 (TLR4)/nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase isoform 2 (NOX2) pathway to clear ROS. This study reveals the molecular mechanism of MnO nanozymes modulating microglia phenotype to attenuate neuroinflammation primarily through inhibition of the TLR4/NOX2 pathway and highlights the temporal sequence of anti-inflammatory treatment in regulating microglial phenotype and improving fAβ pathology, providing new insights for the anti-inflammatory treatment of AD and other neurological diseases.