Understanding the Modulatory Effects of Cannabidiol on Alzheimer's Disease.

Yinyi Xiong,Chae-Seok Lim

doi:10.3390/brainsci11091211

Abstract

Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by progressive cognitive impairment. The deposition of amyloid beta (Aβ) and hyperphosphorylated tau is considered the hallmark of AD pathology. Many therapeutic approaches such as Food and Drug Administration-approved cholinesterase inhibitors and N–methyl–D–aspartate receptor antagonists have been used to intervene in AD pathology. However, current therapies only provide limited symptomatic relief and are ineffective in preventing AD progression. Cannabidiol (CBD), a phytocannabinoid devoid of psychoactive responses, provides neuroprotective effects through both cannabinoid and noncannabinoid receptors. Recent studies using an AD mouse model have suggested that CBD can reverse cognitive deficits along with Aβ-induced neuroinflammatory, oxidative responses, and neuronal death. Furthermore, CBD can reduce the accumulation of Aβ and hyperphosphorylation of tau, suggesting the possibility of delaying AD progression. Particularly, the noncannabinoid receptor, peroxisome proliferator-activated receptor gamma, has been suggested to be involved in multiple functions of CBD. Therefore, understanding the underlying mechanisms of CBD is necessary for intervening in AD pathology in depth and for the translation of preclinical studies into clinical settings. In this review, we summarize recent studies on the effect of CBD in AD and suggest problems to be overcome for the therapeutic use of CBD.

Highlights

Alzheimer’s disease (AD), which is the most common neurodegenerative disease, is characterized by progressive cognitive deficits before the normal aging process
It is difficult to recapitulate the pathology of hyperphosphorylated tau, which contributes to the formation of neurofibrillary tangles in amyloid precursor protein (APP)-transgenic AD mice, a close link between Aβ accumulation and tau pathology has been reported in induced pluripotent stem cell-derived neurons and three dimensional (3D) organoids of AD [1,2]
CBD is a well-known inverse agonist of cannabinoid receptors, the modulation of which is reported to be beneficial for preventing AD pathology

Summary

Introduction

Alzheimer’s disease (AD), which is the most common neurodegenerative disease, is characterized by progressive cognitive deficits before the normal aging process. The neuroprotective role of CB1 receptor activation through inhibition of Aβ-induced NO production accompanied by reduced gliosis and improved spatial memory in the eight-arm radial maze was observed in an in vivo study [52]. Modulation of the ECS components has been reported to achieve benefits against AD pathology, but the mechanism through which the cannabinoid receptor directly regulates the neuroprotective roles of CBD against AD pathology has not been studied. It remains unclear whether the pharmacological effects of CBD observed in AD therapy are associated with receptors other than PPARγ. Whether excitatory neurons and inhibitory neurons differently respond to CBD in AD pathological conditions should be investigated in the future

Conclusions

Findings

Abbreviation List