Beta amyloid-induced depression of hippocampal long-term potentiation is mediated through the amylin receptor.
J Neurosci
; 32(48): 17401-6, 2012 Nov 28.
Article
em En
| MEDLINE
| ID: mdl-23197731
ABSTRACT
Alzheimer's disease (AD) is characterized by accumulation of amyloid-ß peptide (Aß) in the brain regions that subserve memory and cognition. The amylin receptor is a potential target receptor for expression of the deleterious actions of soluble oligomeric Aß species. We investigated whether the amylin receptor antagonist, AC253, neutralizes the depressant effects of Aß(1-42) and human amylin on hippocampal long-term potentiation (LTP). Furthermore, we examined whether depressed levels of LTP observed in transgenic mice, which overexpress amyloid precursor protein (TgCRND8), could be restored with AC253. In mouse hippocampal brain slices, field EPSPs were recorded from the stratum radiatum layer of the CA1 area (cornu ammonis 1 region of the hippocampus) in response to electrical stimulation of Schaeffer collateral afferents. LTP was induced by 3-theta burst stimulation protocols. Aß(1-42) (50 nM) and human amylin (50 nM), but not Aß(42-1) (50 nM), depressed LTP evoked using both stimulation protocols. Preapplication of AC253 (250 nM) blocked Aß- and human amylin-induced reduction of LTP without affecting baseline transmission or LTP on its own. In contrast to wild-type controls, where robust LTP is observed, 6- to 12-month-old TgCRND8 mice show blunted LTP that is significantly enhanced by application of AC253. Our data demonstrate that the effects of Aß(1-42) and human amylin on LTP are expressed via the amylin receptor, and moreover, blockade of this receptor increases LTP in transgenic mice that show increased brain amyloid burden. Amylin receptor antagonists could serve as potentially useful therapeutic agents in AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Potenciação de Longa Duração
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Polipeptídeo Amiloide das Ilhotas Pancreáticas
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Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas
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Hipocampo
Tipo de estudo:
Guideline
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article