Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-β-induced toxicity

Cinzia Severini, Pamela Petrocchi Passeri, Mariateresa Ciotti, Fulvio Florenzano, Roberta Possenti, Cristina Zona, Anna Di Matteo, Angelo Guglielmotti, Pietro Calissano, Joel Pachter, Delio Mercanti

Research output: Contribution to journalArticlepeer-review

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-β (Aβ) peptides that accumulate in senile plaques. Aβ 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 Aβ, 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 Aβ25-35 and Aβ1-42-induced toxicity in primary mixed neural cultures. Bindarit (30-500 μM) reversed cell death induced by Aβ in a dose-dependent manner and reduced the transcription and release of CCL2 by astrocytes after Aβ 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 Aβ. Bindarit was able to disconnect this neuro-glial interaction. Our results demonstrate the ability of bindarit to inhibit Aβ-induced neuronal death and suggest the potential role of CCL2 inhibitors in the treatment of neuroinflammatory/neurodegenerative diseases.

Original languageEnglish
Pages (from-to)281-293
Number of pages13
JournalJournal of Alzheimer's Disease
Volume38
Issue number2
DOIs
Publication statusPublished - 2014

Keywords

  • Alzheimer's disease
  • amyloid-β toxicity
  • bindarit
  • CCL2
  • neuroinflammation

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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