Mechanistic Insights into Cannabidiol-Mediated TrkB Activation via FRS2 Interaction in Attenuating Alzheimer's Disease Pathology and Cognitive Impairment

Alzheimer’s disease (AD), a leading neurodegenerative disorder, lacks effective treatments due to its complex pathology. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits neuroprotective, anti-inflammatory, and antioxidant properties, suggesting therapeutic potential in AD. However, the molecular target and underlying mechanism through which CBD exerts its effects on AD are not well understood. Here, we show that CBD alleviates synaptic and cognitive deficits in 3×Tg-AD mice, improving learning, memory, and anxiety behaviors. Mechanistically, CBD reduced Aβ accumulation, neuroinflammation, and insulin resistance via the JAK2/STAT3/SOCS1 pathway, and attenuated Tau pathology through the PI3K/AKT/GSK3β axis. By isothemal shift assay, we identified FRS2, an TrkB adaptor protein, as a novel CBD target. Several biophysical techniques were employed to characterize the interaction between CBD and FRS2, revealing a dissociation constant (Kd) in the micromolar range. Furthermore, CBD was shown to increase the thermal stability of FRS2 in cells. Notably, FRS2 knockdown abrogated CBD's protective effects in both cellular and animal models. These findings reveal a previously unrecognized molecular mechanism and therapeutic target of CBD, supporting its development as a potential treatment for AD.