Microglial Endocannabinoid Signalling in AD

Abstract

Chronic inflammation in Alzheimer’s disease (AD) has been recently identified as a major contributor to disease pathogenesis. Once activated, microglial cells, which are brain-resident immune cells, exert several key actions, including phagocytosis, chemotaxis, and the release of pro- or anti-inflammatory mediators, which could have opposite effects on brain homeostasis, depending on the stage of disease and the particular phenotype of microglial cells. The endocannabinoids (eCBs) are pleiotropic bioactive lipids increasingly recognized for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. Here, we review the current literature regarding the involvement of this signalling system in modulating microglial phenotypes and activity in the context of homeostasis and AD-related neurodegeneration.

Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration

“…are also involved in crosstalk between microglia and neurons, as microglia also secretes such factors and both neurons and microglia express their receptors ( Szepesi et al, 2018 ). Accumulating evidence indicates that the microglial endocannabinoid system functions as a “non-canonical” signaling mechanism in the management of neuron–microglia crosstalk, thereby assisting microglia in regulating brain inflammation ( Castillo et al, 2012 ; Scipioni et al, 2022 ). CB1Rs are predominantly expressed in neurons, whereas CB2Rs are characteristic of microglia, especially during neuroinflammation ( Komorowska-Müller and Schmöle, 2021 ).…”

Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer’s disease: A systematic review and meta-analysis of animal studies

“…This literature review presents the first systematic analysis of pre-clinical data on the modulation of glial cells by cannabinoids that affects cognitive performance. Evidence of the impact of glial cell endocannabinoid signaling on cognitive deficits in AD was demonstrated by the attenuation of memory impairment ( Dominicis et al, 2022 ). The summary of the glial cell endocannabinoid mechanisms in cognition extracted from each article is presented in Supplementary Table S2 .…”

“…Cannabinoids elicit CB2R activation in microglia, which is responsible for their immunological effects. For example, CB2R activation inhibits the release of pro-inflammatory mediators, including TNF- α and free radicals, while promoting microglial cell proliferation and migration ( Carrier et al, 2004 ; Dominicis et al, 2022 ). Therefore, activating CB2R in microglia might favorably affect inflammation.…”

“…CB2R activation induces phagocytosis ( Mecha et al, 2015 ) and switches the M1 phenotype of microglial cells to the M2 phenotype ( Orihuela et al, 2016 ). As M2 microglia upregulate endocannabinoid receptor expression, increased endocannabinoid release may, in turn, activate CB1R or CB2R and distinct endocannabinoids signaling cascades, intensifying the M2 profile ( Mecha et al, 2016 ; Dominicis et al, 2022 ). The exposure of rat or human microglia to low concentrations of 2-AG and AEA increases the expression of the M2 marker Arg-1, Ym1/2, along with other markers of alternative phenotype such as suppressor of cytokine signaling 3 (SOCS 3) ( Mecha et al, 2015 ).…”

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

“…Furthermore, it was demonstrated that endocannabinoids or synthetic and natural cannabinoid compounds promote an anti-inflammatory activity in central and peripheral macrophages [ 152 , 192 , 193 ], disclosing a complex immunomodulation by these pleiotropic bioactive lipid messengers.…”