Mitochondrial Lysates Induce Inflammation and Alzheimer's Disease-Relevant Changes in Microglial and Neuronal Cells

作者：Wilkins Heather M; Carl Steven M; Weber Sam G; Ramanujan Suruchi A; Festoff Barry W; Linseman Daniel A; Swerdlow Russell H^*

来源：Journal of Alzheimer's Disease, 2015, 45(1): 305-318.

DOI：10.3233/JAD-142334

• Alzheimer's disease
• amyloid-beta protein precursor
• inflammation
• mitochondria
• mtDNA
• TREM2

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.

• 出版日期2015