Reduced <scp>CB1</scp> Cannabinoid Receptor Expression in Alzheimer's Disease and Transgenic Mouse Models

ABSTRACT Objectives Therefore, in the present study, the CB1 receptor (CB1R) expression in the hippocampal and cortical tissue of a clinically and neuropathologically characterized cohort of AD patients was analyzed. Methods Post‐mortem brain tissue from patients with sporadic AD and non‐demented control subjects was analyzed immunohistochemically, focusing on the hippocampus, medial frontal gyrus, and superior temporal gyrus. CB1R expression levels were measured and correlated with neuropathological hallmarks of AD (amyloid‐β and tau pathology), neuroinflammatory markers (GFAP and IBA1), cognitive status (Reisberg scale), ApoE genotype, and age. Complementary analyzes were performed in two AD mouse models (5xFAD and Tg4‐42). Results CB1R expression was significantly reduced in the hippocampus, medial frontal gyrus, and superior temporal gyrus of AD patients. CB1R levels negatively correlated with both amyloid‐β and tau pathology but showed no association with cognitive performance, neuroinflammatory markers, age, or ApoE genotype. Consistent with the human findings, CB1R expression was also reduced in the cortex of 5xFAD mice and in the hippocampus of Tg4‐42 mice. Conclusions Our data demonstrate a region‐specific downregulation of CB1R in both human AD brains and transgenic mouse models, which correlates with key neuropathological hallmarks of the disease. These findings suggest a potential role for CB1R in AD pathophysiology and support further investigation into its utility as a biomarker or therapeutic target.