Age-related Brain Expression and Regulation of the Chemokine CCL4/MIP-1β in APP/PS1 Double Transgenic Mice

摘要

The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease (AD). Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1 E9 (APP/PS1) double transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from non-transgenic littermates or single mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitation-quantitative PCR confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathological progression associated with amyloid deposition in AD.