Abstract
Background
Alzheimer's disease is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau. Dysregulation of glycogen synthase kinase-3β (GSK3β) promotes tau hyperphosphorylation and amplifies Aβ-induced neurotoxicity, driving pathogenesis. Despite extensive research, current therapies targeting these core mechanisms remain largely ineffective at halting disease progression.
Objective
Based on prior clinical and preclinical evidence, we hypothesize that cannabidiol (CBD), a non-psychoactive phytocannabinoid, may exert multitarget therapeutic effects in AD by modulating Aβ aggregation, tau hyperphosphorylation, and GSK3β activity.
Methods
We investigated CBD's interactions with Aβ-42/40, tau, and GSK3β using molecular docking, molecular dynamics simulations and ADMET predictions.
Results
Our results show that CBD binds to Aβ with binding free energies of −7.81 kcal/mol, −7.46 kcal/mol, and −7.25 kcal/mol, disrupting aggregation by interacting with key residues (HIS6, HIS13, HIS14, GLU14, GLU22, ASP15, and ASP23). MD simulations confirm that CBD destabilizes Aβ's β-sheet structure, preventing fibril formation. CBD binds tau with binding free energies of −9.91 kcal/mol, −9.70 kcal/mol, and −9.66 kcal/mol, disrupting tau aggregation and preventing neurofibrillary tangle formation. MD simulations show that CBD induces structural changes in tau, reducing β-sheet packing and inhibiting tau-tau interactions. CBD also binds to GSK3β with binding energies of −8.94 kcal/mol, −8.51 kcal/mol, and −8.41 kcal/mol, competing with ATP to inhibit its kinase activity and reduce tau phosphorylation. ADMET analysis indicates CBD's favorable oral bioavailability and low toxicity.
Conclusions
These findings support CBD as a promising multitarget therapeutic for AD, warranting further preclinical and clinical investigations.
Keywords
Get full access to this article
View all access options for this article.
References
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
