THE ENDOCANNABINOID SYSTEM MODULATES THE MICROGLIAL RESPONSE AGAINST AN ACUTE BRAIN INJURY IN AN ANIMAL MODEL OF ALZHEIMER’S DISEASE

As resident immune sentinels, microglia navigate the central nervous system (CNS) through dynamic polarization. In Alzheimer's disease (AD), beta-amyloid plaques induce chronic neuroinflammation, triggering microglial activation. We have previously shown that endocannabinoid system is involved in this microglial response and in the neuromodulation of inflammation. Our study investigated how endocannabinoid system signaling modulates these responses, specifically examining the impact of CB₂ receptor deletion on microglial behavior under homeostatic and inflammatory conditions. Using in vivo two-photon microscopy in WT and 5xFAD mice, a model of AD, we characterized microglial dynamics following acute laser-induced injury in awake mice. Our quantitative 2D and 3D analyses reveal that CB₂ deficiency (CB₂KO) significantly alters microglial plasticity in 5xFAD mice. Specifically, these cells showed a diminished ability to extend and retract their projections, indicating impaired environmental surveillance. In CB₂KO mice, we observed a marked reduction in mean fluorescence intensity at the site of injury. This suggests an attenuated chemotactic response and reduced cell recruitment, even within the “primed” environment of the 5xFAD model. These results indicate that CB₂ signaling is a key driver of microglial motility and functional responsiveness. In the context of neurodegeneration, the loss of CB₂-mediated signaling may compromise the brain's innate ability to mount an effective immune response to acute insults, potentially exacerbating the progression of AD-related pathology. Our findings underscore that CB₂ receptor is a key regulator of microglial “fitness” and a potential therapeutic target for restoring homeostatic immune dynamics in the CNS.
PID2022-138461OB-I00, supported by MICIU/AEI /10.13039/501100011033 and by FEDER, UE.