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Mitochondrial lysates induce inflammation and Alzheimer's disease-relevant changes in microglial and neuronal cells

Heather M Wilkins1, Steven M Carl2, Sam G Weber2

  • 1Department 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.

Journal of Alzheimer'S Disease : JAD
|December 25, 2014
PubMed

Insights

Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern (DAMP) that triggers neuroinflammation in Alzheimer's disease (AD) models. This finding suggests mitochondrial dysfunction contributes to AD pathogenesis.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Alzheimer's disease (AD) is characterized by neuroinflammation, with genetic studies linking inflammation-related genes and amyloid-β to its progression.
  • The precise mechanisms driving neuroinflammation in AD remain incompletely understood.

Purpose of the Study:

  • To investigate the hypothesis that mitochondrial damage-associated molecular pattern (DAMP) molecules contribute to neuroinflammation in Alzheimer's disease.
  • To explore the role of mitochondrial components, specifically mitochondrial DNA (mtDNA), in activating neuronal and microglial inflammatory responses.

Main Methods:

  • Neuronal (SH-SY5Y) and microglial (BV2) cell lines were exposed to enriched mitochondrial lysates.
  • Mitochondrial lysates from cells lacking mitochondrial DNA (ρ0 cells) and purified mtDNA were used to assess specific molecular contributions.
  • Key inflammatory markers, including cytokine mRNA levels (TNFα, IL-8), TREM2 mRNA, MMP-8 mRNA, NFκB pathway activation, p38 MAPK phosphorylation, and APP expression, were measured.

Main Results:

  • Mitochondrial lysates induced inflammatory responses in both cell types, including increased TNFα, IL-8, and MMP-8 mRNA in BV2 cells, and increased TNFα mRNA and APP in SH-SY5Y cells.
  • NFκB nuclear translocation and p38 MAPK phosphorylation were observed in BV2 cells, alongside NFκB activation and IκBα degradation in SH-SY5Y cells.
  • Mitochondrial lysates lacking mtDNA did not elicit these inflammatory changes, whereas purified mtDNA (non-PCR amplified) induced TNFα mRNA increase in BV2 cells, implicating mtDNA as a key inflammatory trigger.

Conclusions:

  • Mitochondrial-derived DAMP molecules, particularly mtDNA, can directly induce inflammatory responses in microglial and neuronal cell lines.
  • These findings support the hypothesis that mitochondrial dysfunction and the release of mtDNA contribute to the neuroinflammatory processes observed in Alzheimer's disease.
Keywords:
Alzheimer's diseaseTREM2amyloid-β protein precursorinflammationmitochondriamtDNA

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