P4‐290: Calcineurin disrupts fast axonal transport independently of tau in beta‐amyloid oligomer‐treated hippocampal neurons
Bibliographic record
Abstract
Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD).We have shown that soluble amyloid beta oligomers (AβOs), a causative agent of AD, impede FAT of dense core vesicles (DCVs) through a NMDA glutamate receptor-dependent mechanism that is mediated by glycogen synthase kinase 3-beta (GSK3β). AβOs also induce hyperphosphorylation of the axonal microtubule-associated protein, tau; however, it is controversial how this protein disrupts transport. Our recent data shows that AβOs reduce DCV transport similarly in neurons from wild-type and tau knockout mice, and that these defects occur without concomitant microtubule destabilization. This suggests that tau is insufficient for transport disruption; rather, defects may result from activation of intracellular calcium signaling cascades that negatively regulate FAT. Unregulated calcium influx through NMDARs persistently elevates cytosolic calcium and activates the calcium/calmodulin-dependent phosphatase, calcineurin (CaN). A ctivated CaN relieves inhibition of protein phosphatase 1 (PP1), which in turn activates GSK3β; thus, we investigated whether CaN mediates A β O-induced transport disruption independently of tau. We treated hippocampal neurons from wild-type and tau knockout mice with A βOs and subsequently inhibited CaN with FK506. DCV transport was assessed by live cell imaging of fluorescently-tagged brain-derived neurotrophic factor (BDNF-mRFP). Microtubule stability was verified by semi-quantitative immunocytochemistry. To detect changes in CaN activity and assess their impact on PP1 signaling, we employed an in vitro phosphatase assay and immunoblot analyses of CaN fragmentation and inhibitor-1 (I1), a CaN substrate that enables PP1 activation when dephosphorylated. Inhibition of CaN activity reversed A β O-induced transport defects in wild-type and tau knockout neurons. Induction and rescue of transport defects were unaccompanied by changes in post-translational tubulin modifications that confer or indicate stability. CaN activity and I1 dephosphorylation were elevated by A β Os, reduced by FK506 alone, and normalized in the presence of both agents. No changes in calpain-mediated truncation of CaN were detected, indicating that CaN is activated primarily through non-excitotoxic calcium signaling in our studies. A β Os impair BDNF transport independently of tau by activating CaN. Our findings suggest a novel role for calcium signaling in transport regulation and challenge a requirement for tau in AβO-induced transport disruption and toxicity.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".