Inhibition of the polyamine system counteracts ß-amyloid peptide-induced memory impairment in mice: involvement of extrasynaptic NMDA receptors.
PLoS One
; 9(6): e99184, 2014.
Article
em En
| MEDLINE
| ID: mdl-24921942
In Alzheimer's disease (AD), the ß-amyloid peptide (Aß) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Aß. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Aß. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aß25-35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Aß25-35 (10 µM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Aß-induced nuclear translocation of Jacob was blocked upon application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Aß25-35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Aß25-35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) reversed these effects of Aß25-35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved in Aß pathology.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Poliaminas
/
Sinapses
/
Peptídeos beta-Amiloides
/
Receptores de N-Metil-D-Aspartato
/
Transtornos da Memória
Limite:
Animals
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Alemanha
País de publicação:
Estados Unidos