GENETIC LOAD DETERMINES BEHAVIORAL PHENOTYPE AND THE EXPRESSION OF CB1, CB2 AND GPR55 RECEPTORS IN THE 5XFAD MOUSE MODEL OF ALZHEIMER’S DISEASE
- Dina Medina-Vera, Spain
Abstract
Aims
Alzheimer’s disease (AD) is the most common form of progressive neurodegenerative disease and dementia. The endocannabinoid (eCB) system appears to be a novel therapeutic target to treat AD, as it can modulate a range of aspects of AD pathology. The present study has been designed to explore the expression of the eCB system in a 5xFAD transgenic mouse model of AD, taking into consideration the genetic load of the disease: heterozygous (HTZ) versus homozygous (HZ) conditions.
Methods
Experiments were performed on 11-month-old 5xFAD transgenic mice. The Novel Object Recognition (NOR) test was performed to evaluate cognitive functions. Hippocampus samples were obtained to quantify protein expression of eCB system components, neuroinflammation markers, and ß-amyloid (Aß) plaques.
Results
Based on NOR, anxiety-like behaviour and memory were altered in HTZ and HZ 5xFAD mice. HTZ and HZ 5xFAD animals displayed a clear reduction of the expression of CB1 receptor in hippocampus which is related to memory dysfunction. Importantly, the increased levels of CB2 receptors in the HZ group positively correlates with the accumulation observed of Aß (total Aß, Aß1-40 and Aß1-42), indicating enhanced glial reactivity. Moreover, HZ 5xFAD transgenic mice exhibited increased expression of GPR55 compared to HTZ and non-transgenic mice. Also, HZ group showed an alteration in the eCB production/degradation pathway, favouring the production as a compensatory mechanism.
Conclusions
These results highlight the importance of eCB signalling for the development AD pathogenesis beyond Aß deposition.