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 language | English |
|---|---|
| Pages (from-to) | 281-293 |
| Number of pages | 13 |
| Journal | Journal of Alzheimer's Disease |
| Volume | 38 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- Alzheimer's disease
- amyloid-β toxicity
- bindarit
- CCL2
- neuroinflammation
ASJC Scopus subject areas
- Psychiatry and Mental health
- Geriatrics and Gerontology
- Clinical Psychology
Cite this
Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-β-induced toxicity. / Severini, Cinzia; Passeri, Pamela Petrocchi; Ciotti, Mariateresa; Florenzano, Fulvio; Possenti, Roberta; Zona, Cristina; Di Matteo, Anna; Guglielmotti, Angelo; Calissano, Pietro; Pachter, Joel; Mercanti, Delio.
In: Journal of Alzheimer's Disease, Vol. 38, No. 2, 2014, p. 281-293.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-β-induced toxicity
AU - Severini, Cinzia
AU - Passeri, Pamela Petrocchi
AU - Ciotti, Mariateresa
AU - Florenzano, Fulvio
AU - Possenti, Roberta
AU - Zona, Cristina
AU - Di Matteo, Anna
AU - Guglielmotti, Angelo
AU - Calissano, Pietro
AU - Pachter, Joel
AU - Mercanti, Delio
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - amyloid-β toxicity
KW - bindarit
KW - CCL2
KW - neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=84889606928&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84889606928&partnerID=8YFLogxK
U2 - 10.3233/JAD-131070
DO - 10.3233/JAD-131070
M3 - Article
C2 - 23948942
AN - SCOPUS:84889606928
VL - 38
SP - 281
EP - 293
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 2
ER -