Expression of the Adenosine A2A-A3 Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APPSw,Ind Alzheimer’s Disease Model

Lillo, Alejandro; Raïch, Iu; Lillo, Jaume; Pérez-Olives, Catalina; Navarro, Gemma; Franco, Rafael

doi:10.3390/biomedicines10020214

Cited by 8 publications

(5 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, oligomerisation may be cell type-or brain region-specific. For example, recent reports of A 2A R-A 3 R heteromers show differential brain-region expression, being the highest in striatal neurons compared to the hippocampus or frontal cortex but are also found in microglia [275]. To therapeutically exploit A 2A R-A 3 R, it would be desirable to inhibit A 2A R, thereby removing A 2A R functional antagonism of A 3 R signalling and shifting the balance towards A 3 R activation by endogenous adenosine.…”

Section: Therapeutic Potential Of Targeting Ar Oligomersmentioning

confidence: 99%

Adenosine receptor signalling in Alzheimer’s disease

Trinh

Baltos

Hellyer

et al. 2022

Purinergic Signalling

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A1 and A2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A1 and A2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.

show abstract

Section: Therapeutic Potential Of Targeting Ar Oligomersmentioning

confidence: 99%

Adenosine receptor signalling in Alzheimer’s disease

Trinh

Baltos

Hellyer

et al. 2022

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…An interesting finding related to the A 2A -A 3 heteromer is that it is upregulated in primary microglia of the APP Sw,Ind transgenic model of AD. The receptor heteromer functionality in primary microglia from the transgenic and from the control animals was similar (Lillo et al, 2022). Since the animal model does not present cognitive alterations until an advanced age, there must be protection that lasts for months until the system becomes unbalanced.…”

Section: Heteromers With Potential In Neuroprotective Approachesmentioning

confidence: 86%

Neuroprotection afforded by targeting G protein-coupled receptors in heteromers and by heteromer-selective drugs

Franco

Navarro

2023

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are the target of hundreds of approved drugs. Although these drugs were designed to target individual receptors, it is becoming increasingly apparent that GPCRs interact with each other to form heteromers. Approved drug targets are often part of a GPCR heteromer, and therefore new drugs can be developed with heteromers in mind. This review presents several strategies to selectively target GPCRs in heteromeric contexts, namely, taking advantage of i) heteromer-mediated biased agonism/signalling, ii) discovery of drugs with higher affinity for the receptor if it is part of a heteromer (heteromer selective drugs), iii) allosteric compounds directed against the interacting transmembrane domains and, eventually, iv) antagonists that block both GPCRs in a heteromer. Heteromers provide unique allosteric sites that should help designing a new type of drug that by definition would be a heteromer selective drug. The review also provides examples of rhodopsin-like class A receptors in heteromers that could be targeted to neuroprotect and/or delay the progression of diseases such as Parkinson’s and Alzheimer’s. GPCRs in heteromers (GriH) with the potential to address dyskinesias, a common complication of dopaminergic replacement therapy in parkinsonian patients, are also described.

show abstract

“…The potential role of GPCR heteromers in Alzheimer's disease has been described [92][93][94]. For example, there is evidence that, in primary cultures of microglia, blockade of A 2A receptors results in increased CB 2 R-mediated signaling.…”

Section: Orexin-cannabinoid Heteromer Formation As a Potential Target...mentioning

confidence: 99%

Cannabinoid and Orexigenic Systems Interplay as a New Focus of Research in Alzheimer’s Disease

Rebassa,

Capó,

Lillo

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep–wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB2R–OX1R complex expression, while OX1R antagonism potentiates the neuroprotective effects of CB2R. Specifically, pretreatment with the OX1R antagonist has been shown to strongly potentiate CB2R signaling in the cAMP pathway. Furthermore, the blockade of OX1R can also abolish the detrimental effects of OX1R overactivation in AD. In this sense, CB2R–OX1R becomes a new potential therapeutic target to combat AD.

show abstract

Expression of the Adenosine A2A-A3 Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APPSw,Ind Alzheimer’s Disease Model

Cited by 8 publications

References 88 publications

Adenosine receptor signalling in Alzheimer’s disease

Adenosine receptor signalling in Alzheimer’s disease

Neuroprotection afforded by targeting G protein-coupled receptors in heteromers and by heteromer-selective drugs

Cannabinoid and Orexigenic Systems Interplay as a New Focus of Research in Alzheimer’s Disease

Contact Info

Product

Resources

About