Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic

Abstract

The limited effectiveness of current therapies against Alzheimer's disease (AD) highlights the need for intensifying research efforts devoted to developing new agents for preventing or retarding the disease process. During the last few years, targeting the endogenous cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized CB1 and CB2 receptors, with their endogenous ligands and the enzymes related to the synthesis and degradation of these endocannabinoid compounds. Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain's intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. The present paper summarizes the main experimental studies demonstrating the polyvalent properties of cannabinoid compounds for the treatment of AD, which together encourage progress toward a clinical trial.

Keywords: Alzheimer; CB1 receptor; CB2 receptor; cannabinoids; neuroinflammation; oxidative stress; tau; β-amyloid.

FIGURE 1

Summary of the main findings demonstrating beneficial effects of cannabinoid compounds in AD models. Cannabinoids may target in parallel several processes that play key roles in AD, including Aβ and tau aberrant processing, chronic inflammatory responses, excitotoxicity, mitochondrial dysfunction, and oxidative stress, among others. Clinical data also reveal an improvement in behavioral in patients with AD after treatment with cannabinoids.