Inhibition of the CEBPβ-NFκB interaction by nanocarrier-packaged Carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimer's disease model

Neuroinflammation occurs early in Alzheimer's disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of A beta clearance and disruption of synaptic connection. CEBP beta, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBP beta-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBP beta facilitated the interaction of CEBP beta with the NF kappa B p65 subunit, increasing the transcription of proinflammatory cytokines in the APP/PS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1 beta, TNF alpha and IL-6 production in the APP/PS1 mouse brain. CA administration reduced beta-amyloid (A beta) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBP beta with NF kappa B p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NF kappa B target genes TNF alpha and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced A beta secretion by inhibiting the CEBP beta-NF kappa B signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBE beta CD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBE beta CD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.

Automated summary

Neuroinflammation occurs early in Alzheimer's disease, and this study found that carnosic acid can alleviate inflammatory mediator-induced neuronal degeneration and reduce A beta secretion through inhibiting the CEBP beta-NF kappa B signaling pathway, providing potential therapeutic agents for AD treatment.