Targeting glutamatergic and cellular prion protein mechanisms of amyloid ß-mediated persistent synaptic plasticity disruption: Longitudinal studies.
Neuropharmacology
; 121: 231-246, 2017 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-28390893
ABSTRACT
Alzheimer's disease amyloid-ß (Aß) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aß. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aß oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aß on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aß oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Potenciación a Largo Plazo
/
Región CA1 Hipocampal
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Receptor del Glutamato Metabotropico 5
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Proteínas Priónicas
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Amiloidosis
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Neuropharmacology
Año:
2017
Tipo del documento:
Article
País de afiliación:
China