Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-ß-induced toxicity.
J Alzheimers Dis
; 38(2): 281-93, 2014.
Article
em En
| MEDLINE
| ID: mdl-23948942
ABSTRACT
One of the hallmarks of Alzheimer's disease (AD), the most common age-related neurodegenerative pathology, is the abnormal extracellular deposition of neurotoxic amyloid-ß (Aß) peptides that accumulate in senile plaques. Aß aggregates are toxic to neurons and are thought to contribute to neuronal loss. Evidence indicates that inflammation is involved in the pathophysiology of AD, and activation of glial cells by a variety of factors, including Aß, appears to be a central event. Among molecules produced during inflammation associated with neuronal death, CCL2, also known as monocyte chemotactic protein-1 (MCP-1), seems to be particularly important. Indeed, CCL2 levels are higher in the cerebrospinal fluid of patients with AD than in controls. In the present study, we demonstrated the protective effect of bindarit (which inhibits CCL2 synthesis) against both Aß25-35 and Aß1-42-induced toxicity in primary mixed neural cultures. Bindarit (30-500 µM) reversed cell death induced by Aß in a dose-dependent manner and reduced the transcription and release of CCL2 by astrocytes after Aß treatment, as revealed by qRT-PCR, ELISA, and immunofluorescence staining. Astroglial activation and CCL2 release was induced by ATP released by damaged neurons through interaction with P2X7 receptors present on astrocyte surface. CCL2, interacting with its cognate receptor CCR2, present on neuron surface, strongly contributes to the toxic activity of Aß. Bindarit was able to disconnect this neuro-glial interaction. Our results demonstrate the ability of bindarit to inhibit Aß-induced neuronal death and suggest the potential role of CCL2 inhibitors in the treatment of neuroinflammatory/neurodegenerative diseases.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Propionatos
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Fármacos Neuroprotetores
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Quimiocina CCL2
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Indazóis
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Neurônios
Limite:
Animals
/
Pregnancy
Idioma:
En
Revista:
J Alzheimers Dis
Assunto da revista:
GERIATRIA
/
NEUROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Itália