Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer’s Disease in a Preclinical Model: A Therapeutic Opportunity

SIMPLE SUMMARY: Alzheimer’s disease (AD) remains a major challenge for the healthcare system worldwide and, to date, no curative treatment is available. This disease is an irreversible progressive dementia that harms memory and cognitive functions, weakening the ability to carry out tasks by themselves. Among the potential targets for developing innovative therapies for AD, the endocannabinoid system has aroused much interest in the scientific community, since it is involved in multiple processes related to AD pathology. A major challenge to understand the role of the cannabinoid system in AD is to characterize how it contributes to the expression of a specific phenotype, from neuropathology to behavior. In the present study, we addressed this challenge by evaluating the expression of the endocannabinoid system in a transgenic mouse model of AD, bearing five familial AD mutations. Our data suggest that there is an association between the cannabinoid receptors and both the cognitive function and inflammatory response characterizing the disease. Moreover, this association is aggravated by genetic factors. From these data, the expression of endocannabinoid and G protein-coupled 55 receptors (GPR55), and endocannabinoid-related enzymes might be candidate markers for the detection of the severity of this neurodegenerative disease, eventually arising as potential therapeutic targets capable of modifying the course of this incapacitating dementia. ABSTRACT: Alzheimer’s disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer’s disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and β-amyloid (Aβ) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aβ’s accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aβ deposition.