Role of Microglia Adenosine A2A Receptors in Retinal and Brain Neurodegenerative Diseases

Mediators of Inflammation, Jul 2014

Neuroinflammation mediated by microglial cells in the brain has been commonly associated with neurodegenerative diseases. Whether this microglia-mediated neuroinflammation is cause or consequence of neurodegeneration is still a matter of controversy. However, it is unequivocal that chronic neuroinflammation plays a role in disease progression and halting that process represents a potential therapeutic strategy. The neuromodulator adenosine emerges as a promising targeting candidate based on its ability to regulate microglial proliferation, chemotaxis, and reactivity through the activation of its G protein coupled receptor (). This is in striking agreement with the ability of blockade to control several brain diseases. Retinal degenerative diseases have been also associated with microglia-mediated neuroinflammation, but the role of has been scarcely explored. This review aims to compare inflammatory features of Parkinson’s and Alzheimer’s diseases with glaucoma and diabetic retinopathy, discussing the therapeutic potential of in these degenerative conditions.

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Role of Microglia Adenosine A2A Receptors in Retinal and Brain Neurodegenerative Diseases

Role of Microglia Adenosine A2A Receptors in Retinal and Brain Neurodegenerative Diseases Ana R. Santiago,1,2,3,4 Filipa I. Baptista,1 Paulo F. Santos,1,3,5 Gonçalo Cristóvão,3 António F. Ambrósio,1,2,3,4 Rodrigo A. Cunha,3,4 and Catarina A. Gomes1,3,4 1Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal 2AIBILI, 3000-548 Coimbra, Portugal 3Center for Neuroscience and Cell Biology, Largo Marquês de Pombal, Universidade de Coimbra, 3004-517 Coimbra, Portugal 4Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal 5Department of Life Sciences, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal Received 2 May 2014; Accepted 20 June 2014; Published 16 July 2014 Academic Editor: Jesús Pintor Copyright © 2014 Ana R. Santiago et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Neuroinflammation mediated by microglial cells in the brain has been commonly associated with neurodegenerative diseases. Whether this microglia-mediated neuroinflammation is cause or consequence of neurodegeneration is still a matter of controversy. However, it is unequivocal that chronic neuroinflammation plays a role in disease progression and halting that process represents a potential therapeutic strategy. The neuromodulator adenosine emerges as a promising targeting candidate based on its ability to regulate microglial proliferation, chemotaxis, and reactivity through the activation of its G protein coupled receptor (). This is in striking agreement with the ability of blockade to control several brain diseases. Retinal degenerative diseases have been also associated with microglia-mediated neuroinflammation, but the role of has been scarcely explored. This review aims to compare inflammatory features of Parkinson’s and Alzheimer’s diseases with glaucoma and diabetic retinopathy, discussing the therapeutic potential of in these degenerative conditions. 1. Introduction1.1. Role of Microglia in Brain Physiology In the central nervous system (CNS), microglial cells participate in innate immunity; microglia can respond to different types of signals, namely the presence of pathogens (extrinsic signals) or to intrinsic signals, namely diffusible mediators released by stressed neurons, astrocytes or microglia (reviewed in [1]). Although the present review mainly focuses on the contribution of microglia to the pathophysiology of neurodegeneration in the brain and the retina, any attempt to interfere with microglia in pathological conditions also needs to take into account the role of microglia in physiological conditions. In the healthy brain, the majority of microglial cells exhibit a ramified phenotype, compatible with a surveillance function of the surrounding environment. This crucial sensor ability is supported by the constant extension and retraction of cellular processes [2, 3]. This dynamics is not random but instead instructed by increased neuronal activity, that activates pannexin-1 hemichannels, triggering the diffusion of signals, namely, ATP, that drive process motility towards that specific neuron [4]. The interconversion between the so-called “surveying” phenotype (considered more adequate, as compared to the old terminology “resting” phenotype) and the “alerted” phenotype can be driven either by external stimuli (e.g., pathogens) or by neural signals. The latter is achieved by direct neuron-microglia contact or by diffusible mediators (reviewed, e.g., in [1]). This activation of microglia drives some immediate responses that mainly consist in (1) production/release of rectifier mediators and (2) phagocytosis of neurons or subcellular components (mainly dendritic spines and synapses). Microglial phagocytosis of neurons or neuronal structures has been mostly studied in pathological conditions (e.g., [5–8]), but it also takes place in nonpathological conditions. In fact, it is a process of particular importance during neurodevelopment, as shown by Tremblay and coworkers [9] in the visual system: light deprivation and the subsequent decrease in the workload of neuronal circuits involved in visual processing lead to the engulfment of synaptic elements by microglia. This physiological process, termed synaptic pruning, is regulated by the immune system; synapses and axons to be phagocytosed are labeled by the complement components C1q and C3, which prompt their selective recognition by microglial cells [10–12]. Synaptic pruning is crucial to normal brain wiring and function and any impairment of this process may impact on neurodevelopment. For instance, this was recently associated with deficits in synaptic transmission, which are paralleled by behavioral abnormalities characteristic of disorders of the autism spectrum and oth (...truncated)


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Ana R. Santiago, Filipa I. Baptista, Paulo F. Santos, Gonçalo Cristóvão, António F. Ambrósio, Rodrigo A. Cunha, Catarina A. Gomes. Role of Microglia Adenosine A2A Receptors in Retinal and Brain Neurodegenerative Diseases, Mediators of Inflammation, 2014, 2014, DOI: 10.1155/2014/465694