title: Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line.
abstract: One of the key classical pathological features of Alzheimer's disease (AD) is the progressive accumulation of amyloid beta (Aβ42) peptides and their coalescence into highly insoluble senile plaque cores. A major factor driving Aβ42 peptide accumulation is the inability of brain cells to effectively clear excessive amounts of Aβ42 via phagocytosis. The trans-membrane spanning, sensor-receptor known as the "triggering receptor expressed in myeloid cells 2" (TREM2; chr6p21) is essential in the sensing, recognition, phagocytosis and clearance of noxious cellular debris from brain cells, including neurotoxic Aβ42 peptides. Recently, mutations in the TREM2 gene have been associated with amyloidogenesis in neurodegenerative diseases including AD. In this report, we provide evidence that aluminum-sulfate, when incubated with microglial cells, induces the up-regulation of an NF-кB-sensitive micro RNA-34a (miRNA-34a; chr1p36) that is known to target the TREM2 mRNA 3'-untranslated region (3'-UTR), significantly down-regulating TREM2 expression. The aluminum-induced up-regulation of miRNA-34a and down-regulation of TREM2 expression were effectively quenched using the natural phenolic compound and NF-kB inhibitor CAPE [2-phenylethyl-(2E)-3-(3,4-dihydroxyphenyl) acrylate; caffeic-acid phenethyl ester]. These results suggest, for the first time, that an epigenetic mechanism involving an aluminum-triggered, NF-kB-sensitive, miRNA-34a-mediated down-regulation of TREM2 expression may impair phagocytic responses that ultimately contribute to Aβ42 peptide accumulation, aggregation, amyloidogenesis and inflammatory degeneration in the brain.
authors.affiliation: Russian Academy of Medical Sciences, Moscow 113152, Russia.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Alexandrov
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Zhao
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Jones
authors.forename: Surjyadipta
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Lukiw
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000535:Aluminum / Q000494:pharmacology*; D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D002109:Caffeic Acids; C551848:MIRN34a microRNA, mouse; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D016328:NF-kappa B; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D000535:Aluminum; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Aluminum sulfate; Alzheimer's disease; Genotoxicity; Inflammation; Microglial cells; Phagocytosis; TREM2