P2‐120: Inflammasome‐mediated activation of caspase‐1 and caspase‐6 in primary human neurons
Bibliographic record
Abstract
Caspase-6, a key cysteine protease, is up-regulated in Alzheimer disease (AD) neurons and causes axonal degeneration in the absence of cell death. The activation of Caspase-6 is regulated upstream by the inflammatory Caspase-1, a component of a multiprotein complex known as inflammasomes; consisting principally of a nucleotide-binding oligomerization domain (NOD)-like receptor, apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) and Caspase-1. While inflammasome function and intrinsic innate immunity have been well investigated in macrophages, little is known in neurons. In this study we examine the role of intrinsic neuronal immunity in regulating Caspase-6 activation. mRNA and protein expression of the main protein components of the inflammasomes were assessed by quantitative RT-PCR and western blots of primary human neurons. Purinergic P2X7 receptors (P2X7R) were targeted with the agonist benzylated ATP (BzATP) to induce the inflammasome. P2X7R-mediated pore formation was assessed by the uptake of the YO-PRO-1 dye. Caspase-1 and Caspase-6 activity was measured using the fluorogenic substrates Z-YVAD-AFC and Z-VEID-AFC, respectively. P2X7R mRNA was expressed in neurons but not in astrocytes. Treatment of neurons with BzATP induced a considerable uptake of the YO-PRO-1 dye and this uptake was completely inhibited by Brilliant Blue G, a specific P2X7R antagonist. These results indicate that P2X7R activation is opening the pannexin pore. Activation of the inflammasome by BzATP was confirmed by increased Caspase-1 activity. Quantitative RT-PCR showed that inflammasome components, IPAF-1, AIM-2, NALP1, and ASC mRNA were expressed in neurons but only the NALP1 mRNA increased with BzATP treatment. No NALP3 or NALP6 inflammasome receptor expression was observed. BzATP-induced a sequential increase of Caspase-1 YVADase activity and Caspase-6 VEIDase activity within 30 min and 1 hr of treatment, respectively. Blocking Caspase-1 with inhibitor Z-YVAD-fmk reduced Caspase-6 activity in BzATP-treated neurons, confirming that inflammasome formation and Caspase-1 activity are upstream of Caspase-6 activation. These results provide the first characterization of inflammasome components in neurons. Their presence implies that neurons have intrinsic innate immune mechanisms involved in Caspase-1 and Caspase-6 activation. Furthermore, these mechanisms could explain the Alzheimer brain associated increased levels of interleukin-1-beta, a cytokine produced only by Caspase-1.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".