The endocannabinoid system (ECS) is made up of various elements, including cell membrane receptors (CB1, CB2, TRPV1, GPR55), endogenous ligands (called “endocannabinoids”, among which anandamide, AEA, and 2-arachidonylglycerol, 2-AG stand out) and exogenous ligands (such as delta-9-tetrahydrocannabinol, cannabidiol, etc.), as well as the enzymatic machinery of synthesis and degradation of these ligands (such as fatty acid amide hydrolase, FAAH, which degrades AEA, and monoglyceride lipase, MGL, which degrades 2-AG).

Neuroinflammation is a key condition in many neurodegenerative processes, including Alzheimer’s disease (AD). The neuroinflammatory reaction in this disease is caused by the formation of amyloid beta peptide (Aβ) 1-42 and 1-40 oligomers and their deposition in the form of neuritic plaques in the brain parenchyma. These pathological structures, together with the formation of neurofibrillary tangles of hyperphosphorylated tau protein, constitute the main features of AD. Nowadays, SEC is generally considered to be appreciated as part of the endogenous neuroprotective mechanisms available to the CNS and is postulated as a possible target for the treatment of neuroinflammation.

Our research group focuses on two main lines: on the one hand, on the effect derived from the inactivation of the FAAH enzyme in the context of AD and, on the other hand, on the role of the cannabinoid CB2 receptor in neuroinflammatory processes. First, recent data obtained in our laboratory underline the relevance of an increased tone of AEA in relation to: i) basal glial cell activity; ii) acute brain damage; and iii) chronic neuroinflammation. Thus, we have observed that an increase in AEA levels through genetic inactivation of its degradative enzyme, FAAH, alters the activity of astrocyte membrane hemichannels, increases microglial responsiveness after focal brain parenchymal damage and modifies the expression pattern of inflammatory cytokines and enzymes in a murine model of amyloidosis (5xFAD). All these data point to an elevation in the inflammatory cellular environment derived from FAAH inactivation and subsequent increase in AEA levels in the CNS in which interleukin-1 (IL-1) seems to play a prominent role.

On the other hand, our group has recently developed a new experimental tool that can provide relevant data about the role of the cannabinoid CB2 receptor in several pathological processes. This tool is a new transgenic mouse model (CB2eGFP/f/f) that has two fundamental characteristics: i) it is a “reporter” mouse for the CB2 receptor, since the expression of the green fluorescent protein (GFP) takes place under the control of the CB2 receptor promoter region; and, ii) it is, at the same time, a “conditional-knockout” mouse, since the construct used is flanked by two loxp sites. Once we crossed this mouse line with another model of Alzheimer’s disease (5xFAD), we were able to corroborate our hypothesis by observing that CB2 receptor expression in the healthy brain is undetectable while it is significantly increased in the microglia cells located in the vicinity of the beta-amyloid peptide deposits characteristic of this animal model of the disease.