A putative role for PCSK9 in synaptic remodelling and plasticity in response to brain injury: implications for Alzheimer's disease
Notice bibliographique
Résumé
Since the association of the ε4 allele of the apolipoprotein E (apoE) withAlzheimer's disease (AD) risk, growing evidences support a role for cholesterolmetabolism in the pathophysiology of this disease. Many genes involved in lipidmetabolism have now been studied and associate with the risk of AD. PCSK9 is aproprotein convertase recently identified as the third gene linked to familialhypercholesterolemia. It is a key regulator of plasma cholesterol concentrations byenhancing the degradation of cell surface low-density-lipoprotein receptor (LDLR). Thepresent project derives from the global hypothesis that in the brain, PCSK9 may play arole in cholesterol homeostasis by regulating the expression of the LDLR proteins undernormal and especially, neurodegenerative conditions.A first study was conducted to evaluate potential variations in PCSK9 expressionin the brain of autopsy-confirmed AD compared to age-matched control subjects. Agenetic association study was also performed to determine the effect of five commonPCSK9 polymorphisms on AD risk and modulation of gene expression. Using theentorhinal cortex lesion (ECL) model in a second study, a role for PCSK9 in reactivesynaptogenesis was evaluated in response to brain damage in this in vivo paradigm inmice. A third study investigated in an in vitro model of reactive neuronal plasticity, theeffect of PCSK9 on synaptogenesis and remodelling processes in response to neuronalinjury.The results show a cortical and hippocampal upregulation of PCSK9 expression inthe brain of end-stages AD patients which do not result from the five studied geneticvariants. No correlations were observed for PCSK9 with markers of AD pathology;suggesting an involvement of PCSK9 in response to neurodegeneration. Consistent withthis idea, PCSK9 levels were increased during the active phase of neuronal membraneremodelling following ECL. In vitro, overexpression of PCSK9 in normal or neuronallikecells undergoing post-injury reactive plasticity caused increased synaptic densitywhich supports a role for PCSK9 in synaptogenesis and plasticity. While PCSK9 wasfound to negatively affect the LDLR levels in AD brains and both the LDLR and apoER2during reactive plasticity in vitro, levels of the LDLR in ECL mice was not affected byPCSK9 but instead, together with apoE, levels were upregulated in the early phase ofsynaptic remodelling.Together, these findings indicate that PCSK9 plays an important role incompensatory neuronal repair associated with age, brain injury or chronic degeneration asfound in AD. Its expression in the brain possibly regulates cholesterol homeostasis and/orsignalling pathways mediated by the apoE/LDLR pathway or other members of theLDLR family during axonal and synaptic remodelling. These findings are consistent withthe relationship that exists between lipid homeostatic processes and AD pathology andindicate that PCSK9 may be a new player in the regulation of these processes that worthsfurther investigation in a context of neurodegenerative disorders.
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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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».