CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and progressive neuronal loss. The endocannabinoid system regulates synaptic function, inflammation, and redox homeostasis through cannabinoid receptor type 1 (CB1). This study aimed to determine whether pharmacological activation or inhibition of the CB1 receptor differentially modulates Alzheimer's disease-related pathology. 3xTg-AD mice received weekly intraperitoneal injections of the CB1 agonist ACEA (1 mg/kg) or the inverse agonist AM251 (1 mg/kg) from 6 to 12 months of age. Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze, while hippocampal tissues were analyzed for Aβ, p-Tau, glial markers (GFAP, Iba-1), cytokines (IL-1β, IL-10), oxidative stress markers (SOD, GSH, MDA), and neuronal viability (NeuN). Cerebral glucose metabolism was evaluated using ¹ ⁸F-FDG positron emission tomography (PET). ACEA administration reduced tau phosphorylation, glial activation, IL-1β expression, and oxidative stress, while increasing IL-10 levels, neuronal preservation, and cerebral glucose metabolism. AM251 treatment aggravated tau pathology, neuroinflammation, oxidative imbalance, and cognitive impairment. Double immunofluorescence demonstrated CB1 receptor colocalization with both Iba-1-positive microglia and GFAP-positive astrocytes, with CB1 predominantly localized to microglia, suggesting a microglia-dependent mechanism underlying CB1-mediated neuroprotection. Aβ levels were not affected by either treatment. Chronic CB1 receptor activation attenuates tau-associated pathology and metabolic dysfunction in 3xTg-AD mice, indicating the therapeutic relevance of CB1 signaling modulation in neurodegenerative disorders.