P4‐086: TAU Modulates BDNF Expression and Mediates Aβ‐Induced Bdnf Down‐Regulation in Animal and Cellular Models of Alzheimer's Disease
Bibliographic record
Abstract
In Alzheimer’s disease (AD), soluble tau is hyperphosphorylated, and some of this population aggregates and precipitates as neurofibrillary tangles (NFTs). This pathological tau is believed to cause neurodegeneration, although a precise toxic mechanism is not well understood. Our previous work showed that brain-derived neurotrophic factor (BDNF), a protein required for neuronal survival and function, is lost in brain tissue from AD and non-AD tauopathies. Thus, we hypothesized that pathological tau down-regulates BDNF. We quantified BDNF mRNA from the cortex of transgenic mice (8c-het and hTau mice) over-expressing wild-type human tau, as well as wild-type human tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells, using qRT-PCR. These models allowed us to examine the effect of excess tau on BDNF expression. Additionally, we quantified BDNF mRNA from amyloid-β over-expressing (APP23) mice and APP23xTauKO to determine if tau mediates amyloid-β induced BDNF down-regulation. We found a significant reduction in BDNF mRNA in both 8c-het and hTau mice compared to non-transgenic control mice. The 8c-het mice exhibit increased tau phosphorylation but do not develop NFTs, while the hTau mice do exhibit NFT pathology, yet both models significantly down-regulate BDNF. We also found a significant reduction in BDNF and BDNF transcript IV in hTau40-transfected SH-SY5Y cells compared to controls. Lastly, we found that APP23 mice, which over-express Aβ, have significantly reduced BDNF expression. However, when crossed with Tau knockout (KO) mice, the resulting APP23xTauKO animals have cortical BDNF expression intermediate between APP23 and wild-type animals and not statistically different from wild-type animals. Our results demonstrate that excess wild-type tau can down-regulate BDNF, and that neither a mutation in tau nor NFTs are required for toxicity as measured by BDNF expression. Furthermore, the partial rescue of BDNF levels by tau knockout suggests that tau contributes to Aβ-induced BDNF down-regulation. Thus, loss of BDNF may mediate tau neurotoxicity, which has profound implications for therapeutic intervention in AD and tauopathies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".