Cannabidiol Alleviates Aβ1-42-Induced Cognitive Deficits and Neuronal Injury Associated with Modulation of the AEA-FAAH-CB1R Axis and BDNF/TrkB Signaling.

Kong Y.; Peng J.; Sun J.; Nie Y. · Biomolecules · 2026

**Background & Methods** This review investigated cannabidiol's (CBD) neuroprotective mechanisms against amyloid-beta 1-42 (Aβ1-42)-induced cognitive deficits using in vivo models with Morris water maze and novel object recognition testing, complemented by ex vivo hippocampal analysis and in vitro PC12 cell studies. The research focused on CBD's effects on endocannabinoid signaling (AEA-FAAH-CB1R axis) and neurotrophic pathways (BDNF/TrkB), with CB1R involvement confirmed through antagonist (AM251) experiments. **Key Findings** • CBD improved cognitive performance in spatial learning and novel object recognition tasks, while reducing hippocampal pathology including tau hyperphosphorylation, synaptic dysfunction (partially restored synaptophysin levels), and neuronal injury induced by Aβ1-42 exposure. • CBD modulated the endocannabinoid system by increasing hippocampal anandamide (AEA) levels, decreasing fatty acid amide hydrolase (FAAH) expression, and restoring CB1 receptor (CB1R) signaling; these effects were partially reversed by CB1R antagonism, indicating mechanistic involvement of this pathway. • CBD enhanced BDNF/TrkB signaling in both in vivo and in vitro models, improving PC12 cell viability and increasing expression of synaptic markers (synaptophysin), CB1R, BDNF, and phosphorylated TrkB, suggesting CB1R-dependent and -independent neuroprotective mechanisms. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a review article (not original research) examining preclinical models with significant limitations. Findings are derived from animal models and cultured cell lines, which have limited direct translational value to human Alzheimer's disease. The study lacks human clinical trials, pharmacokinetic data, and long-term safety assessments. CB1R antagonist experiments provide mechanistic insight but do not establish definitively whether CB1R modulation is primary or secondary to neuroprotection. Hippocampal tissue analysis was descriptive rather than comprehensive proteomic evaluation. These results represent preliminary evidence suggesting CBD's potential neuroprotective mechanisms and warrant further investigation in clinical populations, but cannot yet support therapeutic recommendations for AD patients.

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