Potential and Limits of Cannabinoids in Alzheimer's Disease Therapy

Abstract

Alzheimer's disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy-sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.

Keywords: 2-AG; Alzheimer’s disease; CB1; CB2; FAAH; THC; amyloid-β; anandamide; cannabidiol; cannabinoids.

Figure 1

Schematic representation of the endocannabinoidergic system in the brain. Putative localization of endocannabinoid receptors in the nervous and glia system. Enzymes involved in endocannabinoid biosynthesis and degradation are reported in both pre-and postsynaptic neurons. 2-AG (green) and AEA (blue) are synthesized from phospholipids on demand. Activation of presynaptic CB1 receptors negatively modulates cell calcium influx and the release of GABA and glutamate neurotransmitters in GABAergic and glutamatergic neurons, respectively. Instead, the stimulation of CB1 in astroglia positively modulates calcium influx and glutamate release. Activation of CB2 in microglia negatively affects the release of TNFα and ILs. AA: arachidonic acid; 2-AG: 2-acylglycerol; AEA: anandamide; PPARs: peroxisome proliferator-activated receptors; FAAH: Fatty acid amide hydrolase; MAGL: monoacylglycerol lipase; mGluR metabotropic glutamate receptors; ILs: interleukins; TNFα: tumor necrosis factor-α.

Figure 2

Schematic representation of the biphasic effects of THC.