Cannabidiol Regulates Amyloid-β Plaque Deposition and Astrogliosis in the 5xFAD Transgenic Mouse Model.

Alzheimer's Disease (AD) is marked by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. Cannabidiol (CBD), the major non-psychoactive compound of Cannabis, has demonstrated significant pharmacological potential for the treatment of AD. CBD is known to act on various receptors, including cannabinoid receptor 1 (CB1R) and 2 (CB2R), and peroxisome proliferator activated receptor γ (PPARγ). However, the precise changes in receptor expression in AD, as well as following CBD treatment, remain unclear and inconsistent in literature. To address this, we performed immunohistochemistry and immunoblotting in AD-compromised brain regions, specifically the cortex and the hippocampus. In 5xFAD transgenic (TG) mice, we noted strong deposition of Aβ plaques and glial fibrillary acidic protein (GFAP)- positive astrocytes. However, following CBD treatment, Aβ plaque burden and GFAP accumulation were significantly reduced. We observed increased CB1R expression in the cortex of TG mice, in comparison to age-matched wild-type control mice. CB2R expression changes were insignificant between the two groups, however, following CBD treatment, CB2R expression was significantly increased. Interestingly, we demonstrated PPARγ co-expressed with Aβ plaques in TG mice, and following CBD treatment, PPARγ co-expression increased. Lastly, we demonstrated dysregulations of the PI3K signaling pathway observed in TG mice was ameliorated with CBD treatment. In this study, we attributed the effects of CBD on AD-related biomarkers, particularly decreased Aβ plaque load and neuroinflammation, to the alterations in CB2R and PPARγ expression.