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

Article type: Research Article

Authors: Wilkins, Heather M.^{a; b} | Carl, Steven M.^b | Weber, Sam G.^b | Ramanujan, Suruchi A.^b | Festoff, Barry W.^{a; c; d; e} | Linseman, Daniel A.^f | Swerdlow, Russell H.^{a; b; d; g; *}

Affiliations: [a] Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA | [b] University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA | [c] Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA | [d] Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA | [e] PHLOGISTIX Neurodiagnostics, Lenexa, KS, USA | [f] Department of Biology, University of Denver, Denver, CO, USA | [g] Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA

Correspondence: [*] Correspondence to: Russell H. Swerdlow, MD, University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Tel.: +1 913 588 6970; Fax: +1 913 945 5035; E-mail: [email protected].

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.

Keywords: Alzheimer's disease, amyloid-β protein precursor, inflammation, mitochondria, mtDNA, TREM2

DOI: 10.3233/JAD-142334

Journal: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 305-318, 2015