title: Mitochondrial lysates induce inflammation and Alzheimer's disease-relevant changes in microglial and neuronal cells.
abstract: Neuroinflammation occurs in Alzheimer's disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-β 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 TNFα mRNA, increased MMP-8 mRNA, increased IL-8 mRNA, redistribution of NFκB to the nucleus, and increased p38 MAPK phosphorylation. SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNFα mRNA, increased NFκB protein, decreased IκBα protein, increased AβPP mRNA, and increased AβPP protein. Enriched mitochondrial lysates from SH-SY5Y cells lacking detectable mitochondrial DNA (ρ0 cells) failed to induce any of these changes, while mtDNA obtained directly from mitochondria (but not PCR-amplified mtDNA) increased BV2 cell TNFα 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.
authors.affiliation: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wilkins
authors.affiliation: University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Carl
authors.affiliation: University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Sam G
authors.initials: SG
authors.lastname: Weber
authors.affiliation: University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Suruchi A
authors.initials: SA
authors.lastname: Ramanujan
authors.affiliation: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA PHLOGISTIX Neurodiagnostics, Lenexa, KS, USA.
authors.forename: Barry W
authors.initials: BW
authors.lastname: Festoff
authors.affiliation: Department of Biology, University of Denver, Denver, CO, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Linseman
authors.affiliation: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000648:ultrastructure*; D008928:Mitochondria / Q000737:chemistry* / Q000473:pathology / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000648:ultrastructure*; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000737:chemistry
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D004272:DNA, Mitochondrial; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; TREM2; amyloid-β protein precursor; inflammation; mitochondria; mtDNA