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Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation.
J Neurosci 2005; 25(8):1904-13JN

Abstract

Alzheimer's disease (AD) is characterized by enhanced beta-amyloid peptide (betaA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent betaA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block betaA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after betaA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.

Authors+Show Affiliations

Neurodegeneration Group, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15728830

Citation

Ramírez, Belén G., et al. "Prevention of Alzheimer's Disease Pathology By Cannabinoids: Neuroprotection Mediated By Blockade of Microglial Activation." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 25, no. 8, 2005, pp. 1904-13.
Ramírez BG, Blázquez C, Gómez del Pulgar T, et al. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25(8):1904-13.
Ramírez, B. G., Blázquez, C., Gómez del Pulgar, T., Guzmán, M., & de Ceballos, M. L. (2005). Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 25(8), pp. 1904-13.
Ramírez BG, et al. Prevention of Alzheimer's Disease Pathology By Cannabinoids: Neuroprotection Mediated By Blockade of Microglial Activation. J Neurosci. 2005 Feb 23;25(8):1904-13. PubMed PMID: 15728830.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. AU - Ramírez,Belén G, AU - Blázquez,Cristina, AU - Gómez del Pulgar,Teresa, AU - Guzmán,Manuel, AU - de Ceballos,María L, PY - 2005/2/25/pubmed PY - 2005/10/27/medline PY - 2005/2/25/entrez SP - 1904 EP - 13 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 25 IS - 8 N2 - Alzheimer's disease (AD) is characterized by enhanced beta-amyloid peptide (betaA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent betaA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block betaA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after betaA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/15728830/Prevention_of_Alzheimer's_disease_pathology_by_cannabinoids:_neuroprotection_mediated_by_blockade_of_microglial_activation_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15728830 DB - PRIME DP - Unbound Medicine ER -