RESUMEN
Neuroinflammation occurs early in Alzheimer's disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aß clearance and disruption of synaptic connection. CEBPß, 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 CEBPß-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPß facilitated the interaction of CEBPß with the NFκB 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-1ß, TNFα and IL-6 production in the APP/PS1 mouse brain. CA administration reduced ß-amyloid (Aß) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBPß with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aß secretion by inhibiting the CEBPß-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEßCD) 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 SBEßCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.
