Cannabinoid CB2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer’s Disease

Esteban, Samuel Ruiz de Martín; Benito-Cuesta, Irene; Terradillos, Itziar; Martínez-Relimpio, Ana M.; Arnanz, M. Andrea; Ruiz‐Pérez, Gonzalo; Korn, Claudia; Raposo, Catarina; Sarott, Roman C.; Westphal, Matthias V.; Elezgarai, Izaskun; Carreira, Erick M.; Hillard, Cecilia J.; Grether, Uwe; Grandes, Pedro; Grande, Teresa; Romero, Julián

doi:10.3389/fphar.2022.841766

Cited by 21 publications

(13 citation statements)

References 38 publications

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“…We detected in the electron microscope the presence of plaques and a multitude of dystrophic neurites in the 5xFAD/CB 2 EGFP/f/f mice that confirms the usefulness of this animal model for studying the pathophysiology of AD (Ruiz de Martín Esteban et al, 2022). We also observed an overt microglial and astrocytic reactivity with an increase in the area and perimeter of their processes, demonstrating the existence of significant alterations in the subicular cytoarchitecture.…”

Section: Discussionsupporting

confidence: 77%

“…We hypothesize in this study that CB 1 receptor expression in glia is altered in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques, as a result of concomitant subcellular changes in microglia and astrocytes. Our findings show that CB 1 receptors in microglial cells suffer remarkable modifications in 5xFAD/CB 2 EGFP/f/f mice, a murine model of AD recently reported to have an increase in CB 2 receptors in microglia related to dystrophic neurites (Ruiz de Martín Esteban et al, 2022), similarly to the CB 2 rise observed in plaque‐associated microglia (Benito et al, 2003, 2007).…”

Section: Introductionsupporting

confidence: 71%

“…Experiments were done in 6.5–7.5‐month‐old male CB 2 EGFP/f/f mice, controls and co‐expressing five AD mutations (5xFAD; Oakley et al, 2006) previously used in our laboratory for the localization of CB 2 receptors (Ruiz de Martín Esteban et al, 2022). The CB 2 EGFP/f/f mice were generated at the Genoway facilities (Lyon, France) by designing a targeting strategy consisting of the insertion of an enhanced green fluorescent protein (EGFP) reporter gene, preceded by an internal ribosomal entry site sequence (IRES) into the 3′ untranslated region (UTR) of the mouse cnr2 gene.…”

Section: Methodsmentioning

confidence: 99%

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Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease

Terradillos

Río

Puente

et al. 2022

Glia

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The alteration of the endocannabinoid tone usually associates with changes in the expression and/or function of the cannabinoid CB 1 receptor. In Alzheimer's disease (AD), amyloid beta (Aβ)-containing aggregates induce a chronic inflammatory response leading to reactivity of both microglia and astrocytes. However, how this glial response impacts on the glial CB 1 receptor expression in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques and concomitant subcellular changes in microglia and astrocytes, is unknown.The CB 1 receptor localization in both glial cells was investigated in the subiculum of male 5xFAD/CB 2 EGFP/f/f (AD model) and CB 2 EGFP/f/f mice by immuno-electron microscopy. The findings revealed that glial CB 1 receptors suffer remarkable changes in the AD mouse. Thus, CB 1 receptor expression increases in reactive microglia in 5xFAD/CB 2 EGFP/f/f , but remains constant in astrocytes with CB 1 receptor labeling rising proportionally to the perimeter of the reactive astrocytes. Not least, the CB 1 receptor localization in microglial processes in the subiculum of controls and closely surrounding amyloid plaques and dystrophic neurites of the AD model, supports previous suggestions of the presence of the CB 1 receptor in microglia. These findings on the correlation between glial reactivity and the CB 1 receptor expression in microglial cells and astrocytes, contribute to the understanding of the role of the endocannabinoid system in the pathophysiology of Alzheimer's disease.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionsupporting

confidence: 71%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease

Terradillos

Río

Puente

et al. 2022

Glia

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“…Further investigations by electron microscopy revealed the presence of low EGFP signal in the membrane of some Iba1-positive cells in the subiculum of CB2 EGFP/f/f mice, and at higher levels in both membrane and cytosol of Iba1-positive cells from CB2 EGFP/f/f /5xFAD mice. 86 In retina, EGFP signal was sparse at baseline in microglial elements, but upregulated following inflammatory stimuli. 87 Efforts must be made to support the development of bettervalidated antibodies in each species in which the CB2R protein is assessed or must be quantified.…”

Section: Con Cluding Remark Smentioning

confidence: 99%

Update on the controversial identity of cells expressing cnr2 gene in the nervous system

et al. 2023

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The endocannabinoid system is recognized as an important player in neuromodulation in the central nervous system (CNS). It comprises cannabinoid receptors, endogenous molecules called endocannabinoids (eCBs) that activate these receptors, and enzymes that synthesize and degrade eCBs. 1 The most abundant eCBs are anandamide and 2-arachidoylglycerol. Many effects of eCBs are mediated by type 1 (CB1R) and type 2 (CB2R) cannabinoid receptors, which are the best known and involved in the homeostatic control of several physiological functions in the brain and other organs. 2 CB1R and CB2R are G protein-coupled receptors (GPCRs) that, in addition to interacting with eCBs, are also activated by synthetic and plantderived cannabinoids. Both were cloned in the early 1990s from human leukemia cells. 3,4 However, it is important to note here that we must take a much broader view of this system. Indeed, studies over the last decade have revealed the existence of a wide range of lipid mediators with eCB-like properties, novel enzymes, and new receptors, effectively complicating our picture of the endocannabinoid system and justifying the use of endocannabinoidome to describe it. 5 CB1R is the most prevalent GPCR in the CNS and is expressed extensively by most neuron types. 6 This receptor is the major mediator of the psychoactive effects of Cannabis sativa and its derivatives.

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“…Indeed, CB2R EGFP/f/f transgenic mice display no expression of CB2Rs in the healthy CNS, while they show an upregulation in reactive microglia in response to inflammation in mice expressing five familial Alzheimer's disease mutations CB2R EGFP/f/f /5XFAD (López et al, 2018). Using electron microscopy in CB2R EGFP/f/f mice, the same group observed a low expression in microglial cells compared to CB2R EGFP/f/f /5xFAD mice (Ruiz de Martín Esteban et al, 2022).…”

Section: Microglial Cb2r Signaling In Physiological Conditionsmentioning

confidence: 95%

Endocannabinoid signaling in microglia

Marinelli

Marrone

Domenico

et al. 2022

Glia

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Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an antiinflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.

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Cannabinoid CB2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer’s Disease

Cited by 21 publications

References 38 publications

Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease

Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease

Update on the controversial identity of cells expressing cnr2 gene in the nervous system

Endocannabinoid signaling in microglia

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