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"... The non-psychoactive compound derived from the Cannabis sativa plant, called cannabidiol (CBD), was recently found to show promise for protecting brain cells from damage.
Compared to Δ9-tetrahydrocannabinol (THC), the compound in cannabis that elicits feelings of euphoria and alters a user's mental state, CBD is safer and could thus be easier to introduce in clinical settings. ...
Du and her colleagues studied a mouse model of AD known as triple-transgenic AD mice. These are genetically modified mice whose synapses become progressively damaged, following the formation of Tau protein tangles and the accumulation of Aβ. These mice exhibit characteristics that resemble those observed in patients with AD, such as memory loss and anxiety-like behaviors.
First, the researchers treated the mice with CBD six days per week for a total period of 45 days. After this treatment period, they observed the mice's behavior and examined their brains.
Interestingly, they found that the mice's memory had improved after treatment and their anxiety levels appeared lower. In addition, dendritic spines in their brains and the overall structure of synapses (i.e., junctions between neurons) appeared to be restored.
"We next looked at how CBD achieves the effects we observed," said Du. "We found that it activates the TrkB-PI3K-AKT pathway—a critical pathway for neuronal survival and plasticity. ..."
From the abstract:
"Alzheimer’s disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity.
At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis.
Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD.
Molecular dynamics simulations further revealed that CBD stabilizes the FRS2–TrkB interface, thereby facilitating TrkB activation.
Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD."
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