Epigenetic regulation in the progressive pathogenesis in Alzheimer’s disease model

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with deficits of cognition and language. AD patients’ brains contain extracellular plaque and neurofibrillary tangles. Recent studies have demonstrated that epigenetic regulation may play a key role in pathogenesis of AD. In this research, we aimed to study abnormal epigenetic controls including histone modification and miRNA regulation in neuroinflamation neurodegeneration in AD. First, we produced and examined in vivo acute neuroinflammation model induced by lipopolysaccharide (LPS) in young normal mice. Neuroinflammation induced by LPS increased cytokines expression and microglial activation. The mRNA levels of IL-1β significantly increased in the frontal cortex, parietal cortex, hippocampus, and striatum after LPS administration. Iba-1-positive microglial cells increased in the striatum, medial septum, frontal cortex, and hippocampus after LPS treatment. Acute systemic LPS injection in this study could induce in vivo model of neuroinflammation, but it could not induce memory impairment. Second, we determined AD stage-dependent regulation of histone modification for the expression of AD specific markers in vivo AD model mice at 1 month, 5months, and 10 months of age. Valproic acid (VPA, non-selective histone deacetylase (HDAC) inhibitor) administration decreased the mRNA levels of NF-κB and IL-1β in plasma and hippocampus of Tg6799 mice at 10 months of age. After VPA administration, the protein level of NGF significantly increased in hippocampus of Tg6799 mice at 5 months and 10 months of age. Interestingly, VPA improved an impaired memory of Tg6799 mice at 5 months and 10 months of age. HDAC inhibition may be a promising therapeutic target for AD and it needs to be considered in stage-dependent manner. Third, we set up prediction method of microRNA (miRNA) and mRNA associations in AD at early symptomatic- or late-symptomatic stages. We detected the functions of miRNA and mRNA associations in AD pathology using integration analysis. We confirmed our prediction system through metabolism related genes such as arrestin containing domain 3 (ARRDC3), a predicted target of miR-139, miR-340, miR-3095, and miR-3470a. The mRNA level of ARRDC3 was increased in the hippocampus of Tg6799 mice at 4 months of age, compared to same aged littermate (LM) controls. Level of ARRDC3 mRNA was increased in an age-dependent manner in LM controls. ARRDC3 mRNA also showed an age-dependent manner increase in Tg6799 mice. The miR-139 expression showed tendency to increase in hippocampus of Tg6799 mice at 8 months of age, compared to their LM controls. These data help further our understating of the function and mechanism of various miRNA and their target genes in the molecular pathology of AD. Taken together, understanding of AD pathogenesis through epigenetic modification can provide future therapeutic approaches in AD.