Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease

Podlesniy, Petar; Figueiro-Silva, Joana; Lladó, Albert; Antonell, Anna; Sánchez‐Valle, Raquel; Alcolea, Daniel; Lleó, Alberto; Molinuevo, José Luís; Serra, Núria; Trullás, Ramón

doi:10.1002/ana.23955

Cited by 181 publications

(165 citation statements)

References 24 publications

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“…In support of this, induction of mitochondrial fragmentation with Phen, a DNA-damaging agent, leads to a decline in the mitochondrial DNA content and loss of mitochondrial mass in HeLa cells (33). Similarly to the findings in FECD specimens, a low content of mtDNA has been detected in the cerebrospinal fluid of Alzheimer's disease patients and has been postulated to be a causal factor for mitochondrial-driven neurodegenerative processes (34).…”

Section: Discussionmentioning

confidence: 72%

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic

Schmedt

Benischke

et al. 2016

Antioxidants & Redox Signaling

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Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in DCm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release.

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Section: Discussionmentioning

confidence: 72%

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic

Schmedt

Benischke

et al. 2016

Antioxidants & Redox Signaling

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“…7 d). The gene for 18S ribosomal RNA was used as a control for the total amount of genomic DNA in the reaction [27] . Unfortunately, all 4 colonies selected were heterozygous; only 1 of the RANK genes cleaved while preserving the intact gene in the other homologous chromosome.…”

Section: Development Of a Stable Bv2 Rank -/-Cell Line Using Crispr/cmentioning

confidence: 99%

Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

et al. 2017

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Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-κB (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK^-/- BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.

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“…CSF isoprostanes correlate to clinical disease progression in the MCI and dementia stages of AD, especially in APOE e4-carrying patients [166], and may serve as damage response markers. Pilot studies suggest that the levels of oxidative DNA damage repair products are elevated in CSF from mixed vascular and Alzheimer's dementia patients [167], and that reduced levels of mitochondrial DNA in CSF suggest depletion of mitochondria [168], which may reflect oxidative stress, but these studies await replication.…”

Section: Biomarkers For Inflammation Oxidative Stress and Microgliamentioning

confidence: 99%

CSF in Alzheimer's Disease

Zetterberg

Lautner

Skillbäck

et al. 2014

Advances in Clinical Chemistry

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Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease

Abstract: Low content of mtDNA in CSF may be a novel biomarker for the early detection of preclinical AD. These findings support the hypothesis that mtDNA depletion is a characteristic pathophysiological factor of neurodegeneration in AD.

Cited by 181 publications

References 24 publications

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

CSF in Alzheimer's Disease

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Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease

Abstract: Low content of mtDNA in CSF may be a novel biomarker for the early detection of preclinical AD. These findings support the hypothesis that mtDNA depletion is a characteristic pathophysiological factor of neurodegeneration in AD.

Cited by 181 publications

References 24 publications

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Implicating Receptor Activator of NF-&#x03BA;B (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli

CSF in Alzheimer's Disease

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Product

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Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli