期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 45, 期 1, 页码 305-318出版社
IOS PRESS
DOI: 10.3233/JAD-142334
关键词
Alzheimer's disease; amyloid-beta protein precursor; inflammation; mitochondria; mtDNA; TREM2
资金
- University of Kansas Alzheimer's Disease Center [P30AG035982]
- Frank and Evangeline Thompson Alzheimer's Treatment Program Fund
- Hugh and Betty Libby Foundation
- Greater Kansas City Automobile Dealers Association
- Gene and Marge Sweeney Chair
- University of Kansas Landon Center on Aging
- University of Kansas Frontiers Heartland Institute for Clinical and Translational Research
- University of Kansas Medical Center's Biomedical Research Training Program
- NATIONAL INSTITUTE ON AGING [P30AG035982] Funding Source: NIH RePORTER
Neuroinflammation occurs in Alzheimer's disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-beta protein promotes inflammation, our understanding of AD neuroinflammation nevertheless remains incomplete. In this study we hypothesized damage-associated molecular pattern ( DAMP) molecules arising from mitochondria, intracellular organelles that resemble bacteria, could contribute to AD neuroinflammation. To preliminarily test this possibility, we exposed neuronal and microglial cell lines to enriched mitochondrial lysates. BV2 microglial cells treated with mitochondrial lysates showed decreased TREM2 mRNA, increased TNF alpha mRNA, increased MMP-8 mRNA, increased IL-8 mRNA, redistribution of NF kappa B to the nucleus, and increased p38 MAPK phosphorylation. SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNF alpha mRNA, increased NF kappa B protein, decreased I kappa B alpha protein, increased A beta PP mRNA, and increased A beta PP protein. Enriched mitochondrial lysates from SH-SY5Y cells lacking detectable mitochondrial DNA (rho 0 cells) failed to induce any of these changes, while mtDNA obtained directly from mitochondria (but not PCR-amplified mtDNA) increased BV2 cell TNF alpha mRNA. These results indicate at least one mitochondrial-derived DAMP molecule, mtDNA, can induce inflammatory changes in microglial and neuronal cell lines. Our data are consistent with the hypothesis that a mitochondrial-derived DAMP molecule or molecules could contribute to AD neuroinflammation.
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