Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer's Disease

Abstract

The pathogenesis of Alzheimer's disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the microglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.

Keywords: Alzheimer's disease; CB1 receptors; CB2 receptors; dementia; endocannabinoid system; new therapeutic approach..

Fig. (1)

Summary of the beneficial effects of the cannabinoid compounds in Alzheimer's disease pathology. Cannabinoid treatment can modulate multiple disease processes including Aβ and tau processing, neuroinflammation, microglial activation, mitochondrial dysfunction and excitotoxicity. CB2 receptor agonists reduce the release of pro-inflammatory molecules, facilitate Aβ clearance by promoting microglia phagocytic phenotype, reduce Aβ neurotoxicity. Moreover, CB2-mediated activity reduces oxidative stress damage produced by reactive oxidative species (ROS) and tau hyperphosphorylation. CB1 receptor agonists regulate iNOS protein expression and NO production, inhibit hyperphosphorylation of tau protein through the inhibition of tau kinase, reduce Abeta plaque load throught the activation of PPAR gamma receptor and the stimulating the expression of LPRP1. 337x257mm (96 x 96 DPI).