Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation

By Belén G. Ramírez, C. Blázquez, Teresa Gómez del Pulgar, M. Guzmán, M. L. de Ceballos. Journal of Neuroscience, 2005

768 citations recorded by the source corpus.

Alzheimer's disease (AD) is characterized by enhanced β-amyloid peptide (βA) 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 βA 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 βA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block βA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-α 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 βA 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.

Subfields: Biological Psychiatry, Cellular and Molecular Neuroscience, Pharmacology

View Paper: https://www.semanticscholar.org/paper/2f4b0e8f0c5757d2fd27c86a8a154b944669d001

How researchers see this paper

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In Cellular and Molecular Neuroscience

1. U. Kumar
2. Shenglong Zou
3. V. Di Marzo
4. P. Pacher
5. S. Batkai
6. George Kunos

In Pharmacology

1. V. Di Marzo
2. U. Kumar
3. Shenglong Zou
4. George Kunos
5. P. Pacher
6. S. Batkai

Citations in the corpus

• Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System (2018, background): “Similarly, although changes of CB1R expression in AD patients or animal models are still controversial, the activation of the CB1R has been shown to prevent amyloid β-induced neurotoxicity in several cell models [139,140,141,142,143,144].”
• The Endocannabinoid System as an Emerging Target of Pharmacotherapy (2006, background): “Senile plaques in AD patients express both CB1 and CB2 receptors together with markers of microglial activation, and CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation (Ramirez et al., 2005).”
• Targeting the endocannabinoid system: to enhance or reduce? (2008, background): “org/GPCR/ReceptorDisplayForward?receptorID=2207">CB 2 receptor activation might either counteract or contribute to β-amyloid-induced gliosis , neuronal damage and memory-retention los”