期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 128, 期 -, 页码 267-269出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2013.05.010
关键词
Aluminum sulfate; Alzheimer's disease; Genotoxicity; Microglial cells; Inflammation; Phagocytosis; TREM2
资金
- Alzheimer Association [IIRG-09-131729]
- NIH NIA [AG18031, AG038834]
One of the key classical pathological features of Alzheimer's disease (AD) is the progressive accumulation of amyloid beta (A beta 42) peptides and their coalescence into highly insoluble senile plaque cores. A major factor driving A beta 42 peptide accumulation is the inability of brain cells to effectively clear excessive amounts of A beta 42 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 A beta 42 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-kappa B-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 NE-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 A beta 42 peptide accumulation, aggregation, amyloidogenesis and inflammatory degeneration in the brain. Published by Elsevier Inc.
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