Cannabidiol Inhibits Tau Aggregation In Vitro

Soha Alali,Gholamhossein Riazi,Mohammad Reza Ashrafi-Kooshk,Mohammad Hooshyari Ardakani,Baharak Hosseinkhani,Sogol Meknatkhah,Shahin Ahmadian

doi:10.3390/cells10123521

Soha Alali, Gholamhossein Riazi + Show 5 more

Open Access

https://doi.org/10.3390/cells10123521

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Abstract

A hallmark of Alzheimer’s disease (AD) is the accumulation of tau protein in the brain. Compelling evidence indicates that the presence of tau aggregates causes irreversible neuronal destruction, eventually leading to synaptic loss. So far, the inhibition of tau aggregation has been recognized as one of the most effective therapeutic strategies. Cannabidiol (CBD), a major component found in Cannabis sativa L., has antioxidant activities as well as numerous neuroprotective features. Therefore, we hypothesize that CBD may serve as a potent substance to hamper tau aggregation in AD. In this study, we aim to investigate the CBD effect on the aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods in vitro and in silico. Using Thioflavin T (ThT) assay, circular dichroism (CD), and atomic force microscopy (AFM), we demonstrated that CBD can suppress tau fibrils formation. Moreover, by quenching assay, docking, and job’s plot, we further demonstrated that one molecule of CBD interacts with one molecule of tau protein through a spontaneous binding. Experiments performed by quenching assay, docking, and Thioflavin T assay further established that the main forces are hydrogen Van der Waals and some non-negligible hydrophobic forces, affecting the lag phase of tau protein kinetics. Taken together, this study provides new insights about a natural substance, CBD, for tau therapy which may offer new hope for the treatment of AD.

Highlights

Alzheimer’s disease (AD) is an irreversible devastating neurodegenerative disease that is mainly diagnosed by memory impairment and cognitive decline due to the slight disruption in the function of the cerebral cortex and hippocampus [1]
Many studies have been so far examined the neuroprotective effects of CBD on several neurodegenerative diseases such as AD
Our study provides important steps to study the molecular effect of the CBD inhibitory action on the formation of amyloid fibrils of tau protein

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible devastating neurodegenerative disease that is mainly diagnosed by memory impairment and cognitive decline due to the slight disruption in the function of the cerebral cortex and hippocampus [1]. In NFTs, polymerization, stability, and organization of microtubules are regulated by the microtubule-associated proteins (MAPs) family. A member of the MAPs family, is mostly found in the axons of neurons in the central nervous system whose functions are involved in stability and assembly modulation of microtubules, neurite growth, and kinesin-dependent axonal transportation [3,4]. The isoforms of tau protein are differed by the presence of zero, one or two N-terminal inserts (0N, 1N, or 2N, respectively), as well as the presence of either three (3R) or four (4R) microtubule binding repeats (MTBRs) in the C-terminal half of tau [6]. When 3R and 4R tau isoforms are not at equal ratios, tau aggregation takes place; the underlying mechanism remains unclear [8,9,10]

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