An integrative analysis of miRNA and mRNA expression in the brains of Alzheimer's disease transgenic mice after real-world PM_(2.5)exposure

摘要

Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic mice(AD mice)were exposed to either filtered air(FA)or PM_(2.5)for eight weeks with a real-world exposure system in Taiyuan,China(mean PM_(2.5)concentration in the cage was 61μg/m~3).We found that PM_(2.5)exposure could remarkably aggravate AD mice's ethological and brain ultrastructural damage,along with the elevation of the pro-inflammatory cytokines(IL-6 and TNF-α),Aβ-42 and ACh E levels and the decline of Ch AT levels in the brains.Based on high-throughput sequencing results,some differentially expressed(DE)m RNAs and DE mi RNAs in the brains of AD mice after PM_(2.5)exposure were screened.Using RT-q PCR,seven DE mi RNAs(mmu-mi R-193b-5p,122b-5p,466h-3p,10b-5p,1895,384–5p,and 6412)and six genes(Pcdhgb8,Unc13b,Robo3,Prph,Pter,and Tbata)were evidenced the and verified.Two mi RNA-target gene pairs(mi R-125b-Pcdhgb8 pair and mi R-466h-3p-IL-17Rα/TGF-βR2/Aβ-42/ACh E pairs)were demonstrated that they were more related to PM_(2.5)-induced brain injury.Results of Gene Ontology(GO)pathways and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways predicted that synaptic and postsynaptic regulation,axon guidance,Wnt,MAPK,and m TOR pathways might be the possible regulatory mechanisms associated with pathological response.These revealed that PM_(2.5)-elevated pro-inflammatory cytokine levels and PM_(2.5)-altered neurotransmitter levels in AD mice could be the important causes of brain damage and proposed the promising mi RNA and m RNA biomarkers and potential mi RNA-m RNA interaction networks of PM_(2.5)-promoted AD.