P2‐131: Beta‐amyloid resistance and the Warburg effect: New insight into Alzheimer's disease from old metabolic pathways
Bibliographic record
Abstract
Numerous studies of post-mortem brain tissue have found significant amyloid-plaque deposition in elderly individuals who exhibited no symptoms of Alzheimer's disease (AD). It has been argued that asymptomatic individuals with high plaque accumulation likely had undiagnosed mild cognitive impairment. However, we propose that these individuals may have acquired an innate resistance mechanism to the toxic effects of amyloid-beta (Aβ). To evaluate this hypothesis, we previously cultured nerve cells in concentrations of Aβ that would otherwise be toxic to select for the eventual emergence of surviving clonal populations. Interestingly, Aβ resistant nerve cells exhibited elevated expression of both pyruvate dehydrogenase kinase 1(PDK1) and lactate dehydrogenase (LDHA). PDK1 and LDHA are central mediators of aerobic glycolysis, also known as the Warburg effect, a form of metabolism frequently employed by cancer cells as an anti-apoptotic strategy. We overexpressed cDNAs for either PDK1 or LDHA in an Aβ sensitive nerve cell line (B12). Fluorescence microscopy was performed using the dyes TMRM and Mitotracker Red-ROS to measure mitochondrial membrane potential and ROS production respectively. Immunoblot analysis of cortical tissue extracts from 12 month transgenic AD mice (APPswe/PSEN1dE9) and postmortem AD patients was performed using PDK1 and LDHA specific antibodies. Overexpression of either PDK1 or LDHA in B12 cells conferred resistance to A β and other neurotoxins. In the presence of A β or oxidants control cells underwent mitochondrial hyperpolarization, increased ROS production and cell death. In contrast, cells expressing either PDK1 or LDHA did not exhibit mitochondrial hyperpolarization and ROS production following A β or oxidant exposure. Interestingly, immunoblot analysis of cortical tissue extracts from transgenic AD mice revealed a decrease in both PDK1 and LDHA expression compared to controls. Additionally, post-mortem AD brain sections exhibited a decrease in PDK1 expression compared to control brain samples. These results suggest that overexpression of either PDK1 or LDHA confers resistance to various neurotoxins by decreasing mitochondrial activity and subsequent ROS production. Collectively, these findings indicate that key Warburg effect enzymes play a central role in mediating resistance to the apoptotic effects elicited by Aβ exposure and may explain why some individuals tolerate high levels of A β deposition without developing 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".