Impact of amyloid-beta peptide overproduction on glucocorticoid-related regulation of glutamatergic function in the hippocampus
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».