title: Age-related brain expression and regulation of the chemokine CCL4/MIP-1β in APP/PS1 double-transgenic mice.
abstract: 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. Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1ΔE9 (APP/PS1) double-transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from nontransgenic 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 polymerase chain reaction 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 neuropathologic progression associated with amyloid deposition in Alzheimer disease.
authors.affiliation: From the Neurocognitive Aging Section (MZ, EP, ELS, PRR), and Gene Expression and Genomics Unit (YZ, KGB), National Institutes of Health, National Institute on Aging, Intramural Research Program, Biomedical Research Center, Baltimore, Maryland; and Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC (JSA).
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Allard
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Evelyn
authors.initials: E
authors.lastname: Perez
authors.forename: Edward L
authors.initials: EL
authors.lastname: Spangler
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rapp
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D054407:Chemokine CCL4 / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D051700:Activating Transcription Factor 3; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C103002:Atf3 protein, mouse; D054407:Chemokine CCL4; D005904:Glial Fibrillary Acidic Protein; D053764:Presenilin-1