O4‐03‐03: APOE ISOFORMS DIFFERENTIALLY REGULATE ALZHEIMER'S NEUROINFLAMMATION
Bibliographic record
Abstract
AD is characterized by Aβ accumulation and deposition in the brain. Neuroinflammation occurs in AD brain and plays important roles in neurodegenerative pathology. ApoE4 is a major AD risk factor; while ApoE2 has a protective effect. In this study, we investigated whether ApoE isoforms differentially affect Alzheimer's inflammation using in vivo and in vitro models. ApoE2/APPsw/PS1dE9 and ApoE4/APPsw/PS1dE9 mice were generated and sacrificed at 6-month age. Cytokine ELISA arrays were performed on brain tissue lysates from the mice. Rat astrocytes were treated with 3μM ApoE proteins followed by 5μM Aβ 42. Mouse astrocytes expressing human ApoE isoforms (provided by Dr. D. Holtzman) were also treated with Aβ 42. qPCR and ELISA were performed to quantify the expression of various cytokines in these cells. Transcription factor (TF) array was used to profile over 300 TFs in rat astrocytes treated with Aβ and ApoE isoforms or TFs in human AD brains. TF agonist experiments in astrocytes highlight a potential mechanism. Cytokine ELISA array reveals that the levels of MCP-1, MIP-1α, RANTES, and IFN-γ were significantly higher in the brains of ApoE4/AD relative to ApoE2/AD mice. Experiments with rat astrocytes show that Aβ42 strongly stimulated expression of GRO and IL-6; while lipid-poor recombinant ApoE2 significantly inhibited these gene expression and ApoE4 had no effect. Aβ 42 treatment of mouse astrocytes expressing human ApoE (lipidated) isoforms shows that ApoE4 significantly promoted cytokine expression, while ApoE2 had no differential effect, relative to Aβ42-treatment alone. A number of TFs were activated or inhibited in rat astrocytes treated with Aβ and ApoE isoforms. A top activated TF in ApoE2/Aβ-treatment was the vitamin D receptor (VDR); while VDR was inhibited in human AD brain. Treatment of cells with VDR agonists significantly inhibited Aβ 42 -induced cytokine expression. Stronger inflammatory response was observed in ApoE4/AD mouse brains compared with ApoE2/AD mice. Lipidated ApoE4 promotes Aβ-induced inflammatory response, while lipid-poor ApoE2 inhibits the response, in astrocytes. VDR may be a major signalling pathway by which ApoE isoforms mediate their effects on Aβ-induced inflammatory response. The differential functions of ApoE isoforms in Alzheimer's neuroinflammation may highlight one of the underlying mechanisms for their roles in AD.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".