P2‐174: NUMB PREVENTS NEURODEGENERATION BY REGULATING INTRANEURONAL TAU LEVELS IN AN ISOFORM‐SPECIFIC MANNER
Bibliographic record
Abstract
Intraneuronal accumulation of the microtubule associated protein Tau is largely recognized as an important toxic factor linked to neuronal cell death in Alzheimer's disease (AD) and tauopathies. While there has been progress uncovering the mechanisms that lead to the formation of toxic Tau tangles, less is known about how intraneuronal Tau levels are regulated in health and disease. Based on various studies, including our own, which identified the endocytic adaptor protein Numb as a key regulator of intracellular protein trafficking in neurons, we hypothesized that Numb might control Tau levels. To explore this possibility, we studied retinal ganglion cells (RGCs), which express Numb and were shown to accumulate Tau in models of AD and tauopathies. Conditional inactivation of Numb (cKO) in RGCs caused a sharp increase in monomeric and oligomeric Tau levels and increased axonal blebbing in optic nerves, followed by significant neuronal cell loss in older mice. Interestingly, siRNA-mediated knock-down of Tau in Numb cKO RGCs rescued neuronal cell death in culture, suggesting that increased Tau levels renders cKO RGCs more susceptible to degeneration. While all four isoforms of Numb physically interact with Tau, only one could decrease intracellular Tau levels when overexpressed in a Tau reporter cell line, identifying this isoform as a potential neuroprotective agent for AD and tauopathies. To test this idea, we overexpressed Numb in RGCs of Tau P301S and 3Tg AD mouse models in vitro and in vivo. Remarkably, we found that Numb reduces the number of axonal blebs in mutant RGCs in culture. In vivo, three days after NMDA injury, Numb-treated P301S and 3Tg mice had 50% more RGCs than control-treated mutant mice and were not significantly different than non-transgenic control mice. Taken together, these results uncover Numb as a novel regulator of Tau protein homeostasis in neurons and as a potential neuroprotective agent for AD and tauopathies. As the relative levels of the different Numb isoforms are altered in the cortex of AD patients, these results also suggest that Numb might be involved in the pathophysiology of AD, representing de facto a novel therapeutic target.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".