Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia

Navarro, Gemma; Borroto-Escuela, Dasiel O.; Angelats, Edgar; Etayo, Íñigo; Reyes‐Resina, Irene; Pulido-Salgado, Marta; Rodríguez‐Pérez, Ana I.; Canela, Enric I.; Saura, Josep; Lanciego, José L.; Labandeira-Garcı́a, José Luis; Saura, Carlos A.; Franco, Rafael

doi:10.1016/j.bbi.2017.08.015

Cited by 104 publications

(107 citation statements)

References 55 publications

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“…Δ 9 -THC at high concentrations interacts with GPR55 but this receptor is not expressed in significant amount in untransfected HEK-293T cells (Balenga et al, 2014;Moreno et al, 2014). The effect of the natural compound was first tested in CB 2 R-expressing cells and the results were fully consistent with those previously reported (Navarro, Borroto-Escuela, et al, 2018a).…”

Section: Functional Characterization Of a 2a R-cb 2 R Tetrameric Cosupporting

confidence: 83%

“…As earlier commented, A 2A R is present in microglia surrounding plaques in AD brains but not in microglia from nondemented age‐matched control brains (Angulo et al, ). Upregulation of the CB 2 R is evident in both the brain of AD patients (Benito et al, , ; Grünblatt et al, ; Ramírez, Blázquez, Gómez del Pulgar, Guzmán, & de Ceballos, ; Solas et al, ) and in cultures of microglia treated with LPS plus IFN‐γ (Aso & Ferrer, ; Koppel et al, ; López et al, ; Mecha, Carrillo‐Salinas, Feliú, Mestre, & Guaza, ; Navarro et al, ; Savonenko et al, ; Wu, Hocevar, Foss, Bie, & Naguib, ). The results here presented show that microglia cells significantly express a functional unit constituted by A 2A ‐CB 2 Hets whose expression was markedly increased in activated cells.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, we have reported that microglia from a transgenic AD model has a similar phenotype as that found in primary microglial cultures (from wild type mice) activated by a combination of lipopolysaccharide and interferon γ (IFN-γ). Interestingly, one of the common features was an increased expression of the CB 2 R (Navarro et al, 2018a). It should be noted that transgenic AD models do not display significant neuronal loss and that the cognitive symptoms appear late in the life of the animal.…”

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confidence: 99%

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Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Franco

Reyes‐Resina

Aguinaga

et al. 2019

Glia

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Neuroprotective M2‐skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein‐coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A2A (A2AR) and cannabinoid CB2 (CB2R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB2R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A2AR antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A2A‐CB2 receptor heteromer (A2A‐CB2Het). Particularly relevant is the upregulation of A2A‐CB2Het expression in samples from the APPSw,Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A2A receptors results in increased CB2R‐mediated signaling. This heteromer‐specific feature suggests that A2AR antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.

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Section: Functional Characterization Of a 2a R-cb 2 R Tetrameric Cosupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Franco

Reyes‐Resina

Aguinaga

et al. 2019

Glia

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“…Endocannabinoid system (ECS) is an essential network of lipid particles and receptors, which contributes to the regulatory processes of many physiological functions throughout the human body. The two main endocannabinoid receptors are the cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, which belong to the family of G‐protein‐coupled receptors . CB1 receptors are placed within the central nervous system (CNS) and in peripheral tissues .…”

Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

211

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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“…) and is a key factor in aging‐related diseases (e.g., dementia) (Navarro et al. ). The ECS is composed of long‐chain poly‐unsaturated fatty acid (LC‐PUFA) derivatives (Torres et al.…”

Section: Introductionmentioning

confidence: 99%

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

et al. 2019

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Poor nutrition during pregnancy is a worldwide public health problem. Maternal nutrient reduction ( MNR ) is associated with maternal and fetal stress and a sex‐dependent decrease in nonhuman primate ( NHP ) cognitive performance. Early life stress potentiates epileptogenesis in a sex‐specific manner, and temporal lobe ( TL ) epilepsy is associated with neurocognitive disorders. The endogenous cannabinoid system ( ECS ) demonstrates remarkable developmental changes and plays a key role in aging‐related diseases (e.g., dementia). Baboons have been studied as a natural model of epilepsy and express all ECS system components. We therefore evaluated baboon fetal temporal cortex ECS ontogenic and MNR ‐dependent changes. At 120 days gestational age ( dGA ) (term 185 days), maternal, fetal, and placental morphometry were similar between control and MNR pregnancies. MNR maternal weight gain was decreased compared with controls at 165 dGA independent of fetal sex. In male fetuses, expression of ECS synthesizing and degrading enzymes was gestational age‐dependent, with the exception of fatty acid amide hydrolase ( FAAH ). MNR had a sex‐specific effect on the protein expression of CB 1R during development: CB 1R protein expression was decreased in fetal temporal cortex of male fetuses at 120 and 140 dGA . Our data reveal that the MNR has sex‐specific effects on temporal cortical expression of the ECS in baboon offspring and shows vulnerability of ECS in male fetuses during gestation.

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Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia

Cited by 104 publications

References 55 publications

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

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Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia

Cited by 104 publications

References 55 publications

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

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Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists