Impact of amyloid-beta peptide overproduction on glucocorticoid-related regulation of glutamatergic function in the hippocampus
Bibliographic record
Abstract
Alzheimer's disease (AD) is a complex disease with unclear etiology. On one hand, pathological hallmarks such as amyloid plaques have been identified. On the other hand, risk factors such as aging, type 2 diabetes, stress and hypercholesterolemia have been associated with AD. The interaction between amyloid pathology and stress may be partly responsible for the etiology of AD, since abnormal activities of hypothalamic-pituitary-adrenal (HPA) axis have been observed in AD patients. In addition, cognitive function, which is impaired in AD, is highly sensitive to stress and stress hormone corticosterone (CORT). The interaction between Aβ peptide and stress could have an impact on the cognitive impairments seen in AD, such as episodic memory deficits that are related to impaired hippocampal function and synaptic plasticity. Hippocampal-dependent synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) depends on glutamatergic receptors activity, such as the N-methyl-D-aspartate receptor (NMDAR) and the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). These glutamate receptor species are highly sensitive to stress and stress hormone. In this proposal, we examined a hypothesis that under a background of overproduction of Aβ peptide stress-induced modulation of NMDAR is affected. Such alteration of stress-induced regulation of NMDAR in the hippocampus could be related to the impact of stress on the pathogenesis of cognitive impairment in AD.To test the hypothesis that overproduction of Aβ peptide affects stress-induced regulation of NMDAR in hippocampal synapses, we compared the influences of stress and stress hormone CORT to synaptic NMDAR function in wild type (WT) and McGill-Thy1-APP mice, an animal model that overexpressed mutated genes of amyloid precursor proteins. At 3 month old, McGill-Thy1-APP mice displayed deficits in hippocampus-dependent memory formation. Using electrophysiological approaches, we found that synaptic NMDAR function in McGill-Thy1-APP mice is significantly lower than WT mice. While CORT decreased synaptic NMDAR function in WT mice, it failed to reduce synaptic NMDAR function in McGill-Thy1-APP mice. We also found that acute restraint stress (30 minutes) reduced synaptic NMDAR function in WT mice but not in McGill-Thy1-APP mice. Finally, we found no changes in the protein expression of corticosteroid receptors between WT and McGill-Thy1-APP mice, suggesting that signaling pathways downstream of these receptors could be responsible for the differences in stress-induced modulation of synaptic NMDAR function between these mice.We revealed that overproduction of Aβ peptide in McGill-Thy1-APP mice may lead to a reduction in synaptic NMDAR function and the abolishment of stress-induced regulation of synaptic NMDAR function. While the reduction in synaptic NMDAR function in McGill-Thy1-APP mice may underlie the deficits of synaptic plasticity and cognitive deficits of these mice, our findings suggest for the first time that stress-induced modulation of synaptic NMDAR could be impaired during the pathogenesis of AD. Although stress has been suggested to exacerbate the pathogenesis of AD, little is known of the underlying mechanisms. Our findings strongly suggest that synaptic NMDAR function could be a cellular substrate that is influenced by the interaction between Aβ peptide overproduction and stress-induced insults.
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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) | 0.000 | 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".