Cecilia J. Hillard

The alteration of the endocannabinoid tone usually associates with changes in the expression and/or function of the cannabinoid CB 1 receptor. In Alzheimer's disease (AD), amyloid beta (Aβ)‐containing aggregates induce a chronic inflammatory response leading to reactivity of both microglia and astrocytes. However, how this glial response impacts on the glial CB 1 receptor expression in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques and concomitant subcellular changes in microglia and astrocytes, is unknown. The CB 1 receptor localization in both glial cells was investigated in the subiculum of male 5xFAD/CB 2 EGFP/f/f (AD model) and CB 2 EGFP/f/f mice by immuno‐electron microscopy. The findings revealed that glial CB 1 receptors suffer remarkable changes in the AD mouse. Thus, CB 1 receptor expression increases in reactive microglia in 5xFAD/CB 2 EGFP/f/f , but remains constant in astrocytes with CB 1 receptor labeling rising proportionally to the perimeter of the reactive astrocytes. Not least, the CB 1 receptor localization in microglial processes in the subiculum of controls and closely surrounding amyloid plaques and dystrophic neurites of the AD model, supports previous suggestions of the presence of the CB 1 receptor in microglia. These findings on the correlation between glial reactivity and the CB 1 receptor expression in microglial cells and astrocytes, contribute to the understanding of the role of the endocannabinoid system in the pathophysiology of Alzheimer's disease.

It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell–cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to “punch above their weight” as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N‐arachidonoylethanolamine and 2‐arachidonoylglycerol (2‐AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.