CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice.

Abstract

The present study shows that chronic administration of the cannabinoid receptor type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AβPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-β (Aβ) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of Aβ42 oligomers in primary cultures of cortical neurons, and reverses Aβ-induced dephosphorylation of glycogen synthase kinase-3β (GSK3β) in vitro and in vivo. Reduced activity of GSK3β in ACEA-treated mice is further supported by the reduced amount of phospho-tau (Thr181) in neuritic processes around Aβ plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes when compared with age-matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3β inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-γ. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease.

• Authors: Ester Aso, Ernest Palomer, Salvador Juvés, Rafael Maldonado, Francisco J Muñoz, Isidro Ferrer
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 30 Issue 2 Pg. 439-59 ( 2012) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 22451318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Arachidonic Acids
• Neuroprotective Agents
• Presenilin-1
• Receptor, Cannabinoid, CB1
• arachidonyl-2-chloroethylamide
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Alzheimer Disease (drug therapy, prevention & control)
• Amyloid beta-Peptides (genetics)
• Animals
• Arachidonic Acids (pharmacology)
• Astrocytes (drug effects, physiology)
• Cerebral Cortex (cytology)
• Cognition (drug effects)
• Cognition Disorders (drug therapy, prevention & control)
• Disease Models, Animal
• Female
• Gliosis (prevention & control)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Hippocampus (cytology)
• Male
• Mice
• Mice, Transgenic
• Neurons (cytology, drug effects)
• Neuroprotective Agents (pharmacology)
• Pregnancy
• Presenilin-1 (genetics)
• Primary Cell Culture
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)