The Effect of Cardiolipin on Microglial Activation and Microglia‐Mediated Neuronal Death
Bibliographic record
Abstract
Microglia, the immune cells of the brain, become activated in response to a variety of stimuli. Under normal physiological conditions, microglial activation is advantageous, as it produces an acute inflammatory response that helps rid the brain of the noxious stimuli through the release of pro‐inflammatory mediators and cytotoxins, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). When microglial activation is sustained, however, the persistent and non‐specific release of these cytotoxic molecules results in damage to surrounding cells, including neurons and other microglia. Such state of chronic neuroinflammation is a characteristic feature of Alzheimer's disease (AD). Cardiolipin (CL), a phospholipid located in the inner mitochondrial membrane, is significantly reduced in AD brains. The remaining CL is exposed to the high levels of ROS present in AD brains, which modifies the structure of CL and hinders its ability to regulate mitochondrial processes. This results in the further production of ROS and extensive neuron death. The intracellular role of CL is well defined; however, the effects of extracellular CL on microglial activation, and subsequently on neuronal viability, have not been described. We utilized cell culture techniques to study the effects of extracellular CL on the activation of microglia, and their subsequent toxicity towards neurons. BV‐2 murine microglia, as well as human HL‐60 promyelocytic and THP‐1 monocytic cells (microglia models), were exposed to CL in the presence of noxious stimuli for 24 or 48 hours. Pro‐inflammatory mediators including tumor necrosis factor (TNF)‐alpha, monocyte chemoattractant protein (MCP)‐1, ROS and RNS in supernatant were quantified to determine the effect CL has on the secretory profile of activated microglia. Additionally, THP‐1 cell supernatants were transferred onto human SH‐SY5Y neuroblastoma cells (neuron model) to determine whether CL regulates microglia‐mediated neurotoxicity. We discovered that CL decreased the secretion of TNF‐alpha, MCP‐1, ROS and RNS from activated microglial cells. Additionally, CL reduced the cytotoxicity of activated THP‐1 cells towards SH‐SY5Y neuronal cells. These findings indicate that CL may act as a novel intercellular signaling molecule that is capable of reducing microglial activation, as well as neuron death. Further studies will explore glial signaling pathways engaged by CL and reveal its role in neuron‐microglia communication.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".