Ubiquitin‐proteasome system dysfunction induced by Alzheimer's disease‐linked Ab oligomers
Bibliographic record
Abstract
Abstract Background Brain accumulation of the amyloid‐β peptide (Aβ) is a pathological hallmark of Alzheimer’s disease (AD). Considerable evidence indicates that soluble Ab oligomers (AβOs) cause synapse failure/loss and cognitive decline in AD. Evidence further indicates that the ubiquitin‐proteasome system (UPS) is inhibited in AD brains, likely leading to impaired synaptic plasticity and memory. However, the mechanisms underlying UPS dysfunction in AD remain to be elucidated Method Here, we investigated proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes from mice that received an intracerebroventricular (i.c.v.) infusion of AβOs. We further investigated the possible protective actions of UCH‐L1, an enzyme that enhances proteasome‐mediated degradation of target proteins, against the impact of AβOs on hippocampal neurons and memory. Result Exposure to AβOs resulted in decreased proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes. Synaptosomes isolated from the hippocampi of AβO‐infused mice were also inhibited compared to hippocampal synaptosomes from control, vehicle‐infused mice. Treatment with exogenous recombinant UCH‐L1 prevented oxidative stress in AβO‐exposed hippocampal neurons and memory deficit in AβO‐infused mice. Conclusion These results indicate that AβOs inhibit the proteasome, notably at synapses, and suggest that boosting proteasomal proteolysis prevents AβO‐induced neuronal damage and memory deficit.
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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) | 0.001 | 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".