Assessing Cannabidiol as a Therapeutic Agent for Preventing and Alleviating Alzheimer's Disease Neurodegeneration

Abstract

Alzheimer's disease (AD) is a leading neurodegenerative condition causing cognitive and memory decline. With small-molecule drugs targeting Aβ proving ineffective, alternative targets are urgently needed. Neuroinflammation, which is central to AD's pathology, results in synaptic and neuronal damage, highlighting the importance of addressing inflammation and conserving neuronal integrity. Cannabidiol (CBD), derived from cannabis, is noted for its neuroprotective and anti-inflammatory properties, having shown efficacy in neuropathic pain management for epilepsy. To investigate the therapeutic efficacy of CBD in AD and to elucidate its underlying mechanisms, we aimed to contribute valuable insights for incorporating AD prevention recommendations into future CBD nutritional guidelines. Aβ_1-42 was employed for in vivo or in vitro model establishment, CBD treatment was utilized to assess the therapeutic efficacy of CBD, and RNA-seq analysis was conducted to elucidate the underlying therapeutic mechanism. CBD mitigates Aβ-induced cognitive deficits by modulating microglial activity, promoting neurotrophic factor release, and regulating inflammatory genes. The administration of CBD demonstrated a protective effect against Aβ toxicity both in vitro and in vivo, along with an amelioration of cognitive impairment in mice. These findings support the potential inclusion of CBD in future nutritional guidelines for Alzheimer's disease prevention.

Keywords: Alzheimer’s disease; anti-inflammatory; astrocyte; cannabidiol; microglia; neuroprotection.

Figure 1

CBD mitigates Aβ-induced cytotoxicity in SH-SY5Y cells. (A) Experimental design schematic. (B) CBD cytotoxicity assessment in SH-SY5Y cells. (C) Effects of CBD on the cell viability of SH-SY5Y cells induced by Aβ_1–42. Data are presented as mean ± SEM (n = 3). * p < 0.05 vs. sham + Veh group; ^# p < 0.05 vs. AD + Veh group; ns: not significant.

Figure 2

Behavioral and cognitive enhancement by CBD in Aβ_1–42-induced mice. Mice were injected with Aβ_1–42 (10 μg, 5 μL, i.c.v.), which was followed by CBD treatment (25 mg/kg, i.g.). (A) Experimental design schematic: (B) average swimming velocities across experimental groups; (C) traversed distances during the test by each group; (D) latency to locate the target platform during the final exploration trial; (E) temporal trend line depicting the duration mice took to reach the target platform during training; (F) swimming paths of mice targeting the hidden platform during the final exploration trial. Data are presented as mean ± SEM (n = 6). * p < 0.05 vs. sham + Veh group; ^# p < 0.05 vs. AD + Veh group, ns: not significant.

Figure 3

CBD’s neuroprotective role and synaptic dysfunction alleviation in Aβ_1–42-induced mice. (A) Quantified image showing the mRNA expression level of Glua1. (B) Quantified image showing the mRNA expression level of Glua2. (C) Quantified image showing the mRNA expression level of CamKIIα. (D) Quantified image showing the mRNA expression level of CamKIIβ. (E) Quantified image showing the mRNA expression level of Syp. (F) Quantified image showing the mRNA expression level of Dlg4. (G) Quantified image showing the mRNA expression level of BDNF. (H) Quantified image showing the mRNA expression level of GDNF. Data are shown as mean ± SEM (n = 4). * p < 0.05 vs. sham + Veh group; ^# p < 0.05 vs. AD + Veh group.

Figure 4

CBD’s modulation of inflammatory responses in Aβ_1–42-induced mice. (A) Quantified image showing the mRNA expression level of TNF-α. (B) Quantified image showing the mRNA expression level of MCP1. (C) Representative fluorescence micrographs showing IBA1 expression in the cortex (scale bar: 200 μm) and quantification of the total number of IBA1⁺ cells in the cortex. (D) Representative fluorescence micrographs showing IBA1 expression in the DG and CA2 regions of the hippocampus (scale bar: 200 μm) and quantification of the total number of IBA1⁺ cells. (E) Representative fluorescence micrographs showing GFAP expression in the DG and CA2 regions of the hippocampus (scale bar: 200 μm) and quantification of the total number of GFAP⁺ cells. Data are shown as mean ± SEM (n = 3). * p < 0.05 vs. sham + Veh group; ^# p < 0.05 vs. AD + Veh group.

Figure 5

Revealing the underlying mechanisms of CBD’s anti-inflammatory effects. (A) Heatmap of DGEs in CBD-treated Aβ_1–42-induced mice and Aβ_1–42-induced mice. (B) Volcano plot of differentially expressed GO pathways in CBD-treated Aβ_1–42-induced mice compared to Aβ_1–42-induced mice. (C) Heatmap of the result of GSVA in CBD-treated Aβ_1–42-induced mice and Aβ_1–42-induced mice. (D) Sankey image showing the result of the gene expression related to the inflammation pathways. (E) Quantified image showing the mRNA expression levels of genes in the negative regulation of respiratory bursts involved in the inflammatory response pathway. (F) Quantified image showing the mRNA expression level of genes in the positive regulation of the neuroinflammatory response pathway. Data are shown as mean ± SEM (n = 3). * p < 0.05 vs. sham+Veh group; ^# p < 0.05 vs. AD+Veh group, ns: not significant.

Figure 6

Schematic overview of CBD’s neuroprotective mechanism in Aβ-induced impairments. CBD can potentially modulate neuroinflammatory pathways, thus inhibiting inflammatory factor release and reducing synaptic damage. Concurrently, CBD augments neurotrophic factor expression, ensuring neuronal protection and ameliorating cognitive and memory deficits in AD mice. Downward arrows indicate negative regulation and upward arrows indicate positive regulation.