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Review
. 2023 Nov 21;12(23):7201.
doi: 10.3390/jcm12237201.

The Interplay between Cannabinoid Receptors and Microglia in the Pathophysiology of Alzheimer's Disease

Rebecca Ferrisi  1   2 , Francesca Gado  2 , Caterina Ricardi  3 , Beatrice Polini  3 , Clementina Manera  1 , Grazia Chiellini  3
Affiliations
Review

The Interplay between Cannabinoid Receptors and Microglia in the Pathophysiology of Alzheimer's Disease

Rebecca Ferrisi et al. J Clin Med. .

Abstract

Alzheimer's disease (AD) is characterized by massive neuronal death, brain atrophy, and loss of neurons and synapses, which all lead to a progressive cognitive decline. Neuroinflammation has been recently identified as one of the main causes of AD progression, and microglia cells are considered to have a central role in this process. Growing evidence suggests that cannabinoids may be used as preventive treatment for AD. An altered expression of the endocannabinoids (eCBs) and their receptors (CBRs) is reported in several neurodegenerative disorders, including AD. Moreover, the modulation of CBRs demonstrated neuroprotective effects in reducing aggregated protein deposition, suggesting the therapeutic potential of natural and synthetic CBR ligands in the treatment of neurodegenerative proteinopathies. Here, we review the current knowledge regarding the involvement of CBRs in the modulation of microglia activation phenotypes, highlighting the role of neuroinflammation in the pathogenesis of neurodegenerative diseases, like AD. We also provide an overview of recently developed candidate drugs targeting CBRs that may afford a new innovative strategy for the treatment and management of AD.

Keywords: cannabinoid receptors; microglia; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CB2R and microglial polarization. (A) CB2R activation in resting microglia (M0) results in increased microglial motility. Activation of microglia (M1, pro-inflammatory microglia) by IFN-γ increases CB2R expression, whereas activation by a combination of IFN-γ/LPS or LPS decreases CB2R expression and increases the secretion of pro-inflammatory cytokines (e.g., TNFα, IL-1β, iNOS). Stimulation of CB2R with agonists causes a switch from the M1 to M2 phenotype (anti-inflammatory microglia). M2 microglia upregulate CB2R, decrease the secretion of pro-inflammatory cytokines, and increase the expression of anti-inflammatory cytokines (e.g., IL-1β, Arg1). (B) Deletion of microglial CB2R leads to a suppression of the pro-inflammatory phenotype. Stimulation of microglia with IFNγ/LPS decreases the secretion of pro-inflammatory cytokines and the expression of inflammatory markers. Similarly, alternative activation of microglia by IL-4 + IL-13 does not take place, as Arg1 remains decreased. Small arrows represent the direction of the effects: increase (↑) or decrease (↓). The green arrow refers to an increase in CB2R, and the purple arrow refers to a decrease in CB2R.
Figure 2
Figure 2
Schematic representation of anti-inflammatory and neuroprotective actions of CB modulators. The pharmacological activation of central CB receptors with CB1R (red), and CB2R (blue) agonists is a promising therapeutic approach for the treatment of AD, since it promotes anti-inflammatory and neuroprotective effects.
Figure 3
Figure 3
Chemical structures of CBR ligands involved in the modulation of microglia activation.
See this image and copyright information in PMC

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