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Microglia Receptors and Their Implications in the Response to Amyloid Β for Alzheimer’S Disease Pathogenesis Deborah Doens1,2 and Patricia L Fernández1*

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Microglia Receptors and Their Implications in the Response to Amyloid Β for Alzheimer’S Disease Pathogenesis Deborah Doens1,2 and Patricia L Fernández1* Doens and Fernández Journal of Neuroinflammation 2014, 11:48 JOURNAL OF http://www.jneuroinflammation.com/content/11/1/48 NEUROINFLAMMATION REVIEW Open Access Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis Deborah Doens1,2 and Patricia L Fernández1* Abstract Alzheimer’s disease (AD) is a major public health problem with substantial economic and social impacts around the world. The hallmarks of AD pathogenesis include deposition of amyloid β (Aβ), neurofibrillary tangles, and neuroinflammation. For many years, research has been focused on Aβ accumulation in senile plaques, as these aggregations were perceived as the main cause of the neurodegeneration found in AD. However, increasing evidence suggests that inflammation also plays a critical role in the pathogenesis of AD. Microglia cells are the resident macrophages of the brain and act as the first line of defense in the central nervous system. In AD, microglia play a dual role in disease progression, being essential for clearing Aβ deposits and releasing cytotoxic mediators. Aβ activates microglia through a variety of innate immune receptors expressed on these cells. The mechanisms through which amyloid deposits provoke an inflammatory response are not fully understood, but it is believed that these receptors cooperate in the recognition, internalization, and clearance of Aβ and in cell activation. In this review, we discuss the role of several receptors expressed on microglia in Aβ recognition, uptake, and signaling, and their implications for AD pathogenesis. Keywords: Cytokines, Inflammation, Microglia, Receptor Background Microglia constitute the lesser portion of the total glial Alzheimer’s disease (AD) is a neurodegenerative disorder cell population within the brain and are found in a rest- characterized by a progressive decline in cognitive and ing state in the healthy central nervous system (CNS) functional abilities. According to the World Health [7]. Under pathological conditions, activated microglia Organization, more than 35 million people have demen- undergo morphological changes and produce cytokines tia and this number is expected to increase in the com- and chemokines that affect surrounding cells [8]. In AD, ing years [1]. The neuropathological hallmarks of AD microglia cells play an important role in disease pro- include extracellular Aβ deposits, intracellular neurofib- gression by clearing Aβ deposits, initiating phagocytic rillary tangles, and marked inflammation [2-4]. Aβ de- activity, and releasing cytotoxic mediators. Microglia position and tau protein are found in different areas of activated by Aβ in vitro induce the expression of proin- the brain, leading to synaptic dysfunction, mitochondrial flammatory cytokines including interleukin (IL)-1β,IL-6, damage, activation of microglia, and neuronal death IL-8, tumor necrosis factor-α (TNF-α), chemokines and re- [5,6]. Inflammation in AD is characterized by reactive active oxygen and nitrogen species, all of which cause microglia surrounding Aβ plaques, which maintain an neuronal damage [9-11]. inflammatory status by secreting proinflammatory medi- The mechanisms through which amyloid deposits pro- ators, contributing to neuronal loss. voke inflammation are not fully understood. Microglia cells express several receptors that cooperate in the rec- ognition, internalization, and clearance of Aβ and in cell * Correspondence: [email protected] 1Centro de Biología Molecular y Celular de Enfermedades, Instituto de activation. Microglia receptors, such as scavenger recep- Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP), tors (SR-AI/II), CD36, RAGE (receptor for advanced Edificio 219, Clayton, Ciudad del Saber, República de Panamá glycosylation endproducts), Fc receptors, TLRs (toll-like Full list of author information is available at the end of the article © 2014 Doens and Fernández; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Doens and Fernández Journal of Neuroinflammation 2014, 11:48 Page 2 of 14 http://www.jneuroinflammation.com/content/11/1/48 receptors), and complement receptors are involved in these high levels of this receptor have been detected in the processes [12-14] (Figure 1). This review will examine the cerebrospinal fluid (CSF) of AD patients [20]. A recent various roles of microglia receptors in the amyloid cascade, genome-wide association study in a Caucasian popula- and the implications for AD. tion showed an association of some variants of CR1 with late-onset AD risk, which has drawn increased attention Complement receptors to the role of this receptor in the pathogenesis of AD [21]. The complement system is formed of a number of sol- Those CR1 variants were further correlated with character- uble and membrane-associated proteins that interact to istic neuroimaging markers of the disease [22]. The associ- opsonize microorganisms and to induce an inflammatory ation between CR1 and AD risk has been reproduced in response that contributes to the resolution of the infec- case-control studies in other populations [23,24]. tious process [15]. The association of the complement Activated microglia have increased expression levels of system with AD pathology has been known since the CR1; activation of this receptor induces neuronal death 1980s [16]. Proteins of the complement system have [25]. These detrimental effects appear to be associated been associated with senile plaques in the brains of AD with enhanced superoxide generation and TNF-α and individuals [17]. Several proteins of the complement sys- IL-1β production. CR1 expressed on erythrocytes partic- tem and their corresponding mRNAs are upregulated in ipates in the clearance of peripheral Aβ, suggesting that the brains of AD patients and seem to be involved in Aβ CR1 may play a role in the removal of Aβ in AD [26]. induced inflammation, senile plaque formation, and Aβ Polymorphisms in the CR1 locus, which constitute a risk phagocytosis [18]. for AD, have been correlated with increased levels of Aβ The activation of the complement system takes place in the CSF [27]. Owing to the role of CR1 in the clear- via three main pathways known as classical, alternative, ance of Aβ and regulation of complement activation, it and MB-lectin [18]. Fibrillar Aβ (fAβ) activates the clas- has been suggested that this receptor may have a benefi- sical as well as the alternative pathways with consequent cial effect on the pathogenesis of AD [28], although the C3 activation, C5a production, and membrane attack mechanisms are unknown. complex (MAC) formation [19]. The role of the comple- The complement factor C3 is an essential component ment system in the removal of the infectious agent occurs of the complement system. It induces phagocytosis of through the activation of a variety of receptors in- pathogens through interactions with the CR3 receptor. cluding CR1 (CD35), CR2 (CD21), CR3 (CD11b/CD18), CR3, also known as Mac-1, is expressed in microglia, CR4 (CD11c/CD18), and C5aR (CD88 and C5L2). Some of and upregulation of this receptor has been detected in these receptors play a prominent role in the inflammatory the brains of AD individuals [29]. Studies have shown response induced in AD [12]. that CR3 appears to be involved in the uptake and clear- CR1 is a transmembrane receptor that plays a major ance of Aβ in vivo and in vitro [30-32]. Fu et al. have re- role in the regulation of the complement cascade activa- cently suggested that CR3 acts together with the scavenger tion. CR1 binds the complement factors C3b and C4b; receptor A (SR-A) in the uptake of Aβ [32]. They also Figure 1 Microglia receptors involved in the amyloid cascade. A variety of microglia receptors are involved in Aβ clearance and in triggering an inflammatory response. Some receptors (RAGE, NLRP3) are mainly implicated in the generation of an inflammatory response by triggering a signaling cascade that results in the production of proinflammatory mediators. Other receptors (SR-AI, TREM2) are involved in the clearance of Aβ by inducing internalization of Aβ fibrils. Some receptors (complement receptors, Fc receptors, FPRL1/FPR2, CD36, TLRs) are involved in both processes. CD33 seems to promote Aβ accumulation. Doens and Fernández Journal of Neuroinflammation 2014, 11:48 Page 3 of 14 http://www.jneuroinflammation.com/content/11/1/48 showed that murine microglia treated with ligands of SR-A these results suggest that activation of complement reduced their capacity for Aβ uptake. receptors may promote the clearance of Aβ, potentially re- CR3 has also been shown to colocalize with Aβ pla- ducing Aβ accumulation and neurodegeneration in AD. ques in the brains of AD patients, providing evidence for More studies are needed to clarify the role of the comple- a possible direct CR3-Aβ interaction [29]. CR3 is par- ment system in the brain and test its potential application tially involved in Aβ activation of microglia in vivo and to the design of novel AD treatments. in vitro and is implicated in microglia free-radical gener- ation in response to Aβ [33]. These effects
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