Protection of Neurons from Apoptosis by Apolipoprotein E-containing Lipoproteins Does Not Require Lipoprotein Uptake and Involves Activation of Phospholipase Cγ1 and Inhibition of Calcineurin
Bibliographic record
Abstract
Apolipoprotein E-containing lipoproteins (LpE) are generated in the central nervous system by glial cells, primarily astrocytes, and are recognized as key players in lipid metabolism and transport in the brain. We previously reported that LpE protect retinal ganglion neurons from apoptosis induced by withdrawal of trophic additives (Hayashi, H., Campenot, R. B., Vance, D. E., and Vance, J. E. (2007) J. Neurosci. 27, 1933-1941). LpE bind to low density lipoprotein receptor-related protein-1 and initiate a signaling pathway that involves activation of protein kinase Cdelta and inhibition of the pro-apoptotic glycogen synthase kinase-3beta. We now show that uptake of LpE is not required for the neuroprotection. Experiments with inhibitors of phospholipase Cgamma1 and RNAi knockdown studies demonstrate that activation of phospholipase Cgamma1 is required for the anti-apoptotic signaling pathway induced by LpE. In addition, the protein phosphatase-2B, calcineurin, is involved in a neuronal death pathway induced by removal of trophic additives, and LpE inhibit calcineurin activation. LpE also attenuate neuronal death caused by oxidative stress. Moreover, physiologically relevant apoE3-containing lipoproteins generated by apoE3 knock-in mouse astrocytes more effectively protect neurons from apoptosis than do apoE4-containing lipoproteins. Because inheritance of the apoE4 allele is the strongest known genetic risk factor for Alzheimer disease, the reduced neuroprotection afforded by apoE4-containing LpE might contribute to the neurodegeneration characteristic of this disease.
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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 | 0.001 |
| 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) | 0.001 | 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".