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Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice
Bivek Chaulagain1, Avinash Gothwal1, Arun Kumar Mahanta1
1Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota 58105, United States.
Abstract:
The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold (p-value < 0.0001), declined pro-inflammatory cytokines TNF-α by 2.51-fold (p-value < 0.0001), IL-1β by 2.34-fold (p-value < 0.0001) and microglial activation by 2.15-fold (p-value < 0.0001) than saline controls. In addition, it increased the synaptic markers level and promoted adult hippocampal neurogenesis, eventually improving cognitive functions. These findings suggest the use of CBD and pBDNF has a potential therapeutic combination for AD management if intervened early.
Insights
Early intervention with cannabidiol (CBD) and brain-derived neurotrophic factor (BDNF) nanoparticles in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Biotechnology
Background:
- Existing Alzheimer's Disease (AD) therapies show limited efficacy due to late-stage intervention when pathology is irreversible.
- Biomarker shifts in AD begin 15-20 years before clinical symptoms manifest.
- Neuroinflammation, amyloid plaques, and tau pathology are key drivers of AD progression.
Purpose of the Study:
- To investigate the potential of early intervention using a novel therapeutic formulation for Alzheimer's Disease.
- To evaluate the efficacy of cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (pBDNF) delivered via targeted nanoparticles.
Main Methods:
- Utilized a 3-month-old 5XFAD AD mouse model for early intervention studies.
- Administered CBD and pBDNF encapsulated in liposome nanoparticles functionalized with penetratin and mannose for brain targeting.
- Assessed therapeutic effects through measurements of amyloid burden, pro-inflammatory cytokines, microglial activation, synaptic markers, and neurogenesis.
Main Results:
- Four weekly doses of the CBD and pBDNF formulation significantly reduced amyloid burden by 3.04-fold (p < 0.0001).
- The treatment markedly declined pro-inflammatory cytokines TNF-α (2.51-fold, p < 0.0001) and IL-1β (2.34-fold, p < 0.0001), and microglial activation (2.15-fold, p < 0.0001).
- The formulation enhanced synaptic markers, promoted adult hippocampal neurogenesis, and improved cognitive functions.
Conclusions:
- Early intervention with CBD and pBDNF nanoparticles demonstrates significant therapeutic potential in an AD mouse model.
- The combination therapy effectively targets key pathological hallmarks of Alzheimer's Disease, including neuroinflammation and amyloid pathology.
- This approach offers a promising strategy for managing Alzheimer's Disease through early, targeted intervention.
