Alzheimer's Disease (AD) and Parkinson's Disease (PD) are the most common neurodegenerative disorders (de Lau and Breteler, 2006). AD involves progressive memory loss and dementia (Sharma and Lipincott, 2017), while the PD is a chronic and progressive movement disorder (Orr et al., 2002). Glaucoma, a neurodegenerative disease of the optic nerve, is characterized by death of retinal ganglion cells (RGCs) (de Hoz et al., 2016). Recently, neurodegenerative lesions have been detected in the intracranial optic nerve, the lateral geniculate nucleus, and the visual cortex (Gupta et al., 2006, 2007), suggesting that this pathology could be grouped as a neurodegenerative disease (Yucel et al., 2003).

AD is a neurodegenerative disorder related to age, in which neuronal and synaptic losses in the cerebral cortex lead to cognitive impairment, behavioral deficits and dementia (Ghiso et al., 2013). The major pathology related to AD is the extracellular deposit of β-amyloid (Aβ) in the form of parenchymal plaques and cerebral amyloid angiopathy co-existing with intraneuronal accumulations of hyperphosphorylated tau (pTau) (neurofribillary tangles) (Ghiso et al., 2013). These deposits can induce neuronal death by apoptosis (Garcia-Ospina et al., 2003). Initially, it was thought that age was the main risk factor for this disease. However, it is now known to have a multifactorial origin and it seems to result from a complex interaction of multiple environmental and genetic factors (Wostyn et al., 2010). AD has been related to genetic mutations, among them in the gene encoding the Aβ precursor protein peptide, mutations in the presenilins genes (Calabrese et al., 2001) and the presence of the APOE ε4 allele (Martínez-Lazcano et al., 2010). In addition, AD is frequently associated with vascular dysfunctions and inflammation (Dudvarski Stankovic et al., 2016).

PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the nerve terminals in the striatum (Dauer and Przedborski, 2003). The clinical symptoms of PD are mainly motor problems, including bradykinesia, rigidity, tremors, and postural instability. In addition, PD presents non-motor symptoms including disorganized speech and altered moods (Fakhoury, 2016). The loss of neurons is accompanied by abnormal intracytoplasmic filamentous aggregates called Lewy bodies. These aggregates (deposited in somas and axons) are constituted by α-syn, parkin, phosphorylated neurofilament and components of the protheosomic-ubiquitin pathway (Orr et al., 2002). The main etiological factors proposed for PD are aging, environmental toxins, and genetic factors. Neurodegeneration could be due to exposure to dopaminergic neurotoxins e.g., herbicides (MPTP), insecticides (Rotenone), and metals (Hernández-Montiel, 2006). Genetic factors include mutations in α-syn (Olanow and Tatton, 1999; Pérez and Arancibia, 2007), while mitochondrial dysfunction and oxidative stress may also act by causing the accumulation of misfolded proteins (Dauer and Przedborski, 2003).

Glaucoma is an age-related multifactorial neurodegenerative disease of the optic nerve, with an irreversible decrease in RGCs, causing a visual-field loss and cupping of the optic nerve head (Quigley et al., 1988). In glaucoma, increased intraocular pressure (IOP), vascular dysregulation, and the immune system activation can trigger several changes in retina and optic nerve including: disrupted axonal transport and neurofilament accumulation, microvascular abnormalities, extracellular matrix remodeling, and glial cell activation. These alterations can lead to secondary damage such as, excitotoxicity, neurotrophin deprivation, oxidative damage, mitochondrial dysfunction, and eventually RGC death (Nickells, 1999; Gallego et al., 2012). In addition, there is a dendritic atrophy of the lateral geniculate nucleus, the site to which the RGC axons project (Gupta et al., 2007; Park and Ou, 2013).

The AD, PD and glaucoma share certain biological features, for example: (i) they are slow and chronic neurodegenerative disorders with a strong age-related incidence; (ii) they have similar mechanisms of cell injury and deposition of protein aggregates in specific anatomical areas (Wostyn et al., 2010; Kaarniranta et al., 2011; Ghiso et al., 2013); and (iii) death occurs in one or more populations of neurons (RGCs in glaucoma, hippocampal and cortical neurons in AD and nigrostriatal dopaminergic neurons in PD) (Mattson, 2000). Although the exact mechanism bringing about this neuronal death remains unknown, these neurodegenerative disorders seem to have pathogenic mechanisms in common. These mechanisms include: oxidative stress (Uttara et al., 2009), mitochondrial dysfunction (Lee et al., 2011; Lascaratos et al., 2012; Chrysostomou et al., 2013), alterations in the ubiquitin-proteasome system (Campello et al., 2013), abnormal accumulation of misfolded proteins, glutamate excitotoxicity (Gazulla and Cavero-Nagore, 2006; Guimaraes et al., 2009), and glial activation and inflammation (Verkhratsky et al., 2014; Brown and Vilalta, 2015). These mechanisms could act individually or synergistically (Ghiso et al., 2013).

Inflammation is a defensive process of the body against damage that seeks to restore tissue integrity. Neuroinflammation, the inflammation of central nervous system (CNS), is essential to protect the tissue. However, uncontrolled and prolonged neuroinflammation is potentially harmful and can cause cellular damage. The astrocytes and microglia could play a major role in the neuroinflammation associated with neurodegenerative diseases (Cherry et al., 2014). The presence of reactive astrocytes, the microglial activation, and the release of inflammatory mediators such as cytokines, reactive oxygen species (ROS), nitric oxide (NO), and Tumor Necrosis Factor-α (TNF-α) could cause a state of chronic inflammation that may exert neurotoxic effects (Cuenca et al., 2014).

The neuroinflammatory process occurs not only in the brain, but also in the retina, which is a projection of the CNS. The retina and brain are associated over a range of neurological and neurovascular conditions of varying etiologies, because the retina and brain are similar, and respond similarly to disease. Thus, it has been described that the retina is a “window to the brain,” and the manifestation of disease in the brain is the same as in the retina (MacCormick et al., 2015). The neuroinflammatory changes could be observed using optical coherence tomography (OCT), a routinely diagnostic techniques used in ophthalmology. This technique provides anatomic detail of pathological changes in the retina and optic nerve. Changes in OCT measurements have been used to study the course of particular neurologic diseases such AD (Garcia-Martin et al., 2014; Maldonado et al., 2015; Salobrar-Garcia et al., 2015, 2016a,b), PD (Yu et al., 2014; Stemplewitz et al., 2015; Boeke et al., 2016; Satue et al., 2017), and glaucoma (Leung, 2016; Fallon et al., 2017), suggesting that the data compiled may be useful as a biomarker in diagnosing and treating neurodegenerative disease.

The aforementioned data underline the importance of knowing the function of inflammatory processes in the retina of neurodegenerative diseases (AD, PD, and glaucoma), especially the contribution to microglial-mediated neuroinflammation.

In neurodegenerative diseases, neuroinflammation constitutes a fundamental process in which microglial cells play a key role (Glass et al., 2010). Microglial cells are CNS resident immune cells which have sensor and effector functions as well as phagocytic capacity (Streit et al., 2005). In the developing of CNS these cells enter from the bloodstream, develop from monocytes, and differentiate into microglia. Thus, they maintain numerous cellular antigens present in macrophages and monocytes (Ransohoff and Cardona, 2010). Microglia express CD11b/c, D45^low, and the chemokine fractalkine receptor (CX3CR1) (Dudvarski Stankovic et al., 2016). These cells survey the CNS in order to detect homeostasis alteration and they respond accordingly, combining a defensive service with neuroprotective functions (Verkhratsky and Butt, 2013).

In addition to the immune functions, microglia have an essential role in the physiology and survival of neurons. Fractalkine, involved in indirect neuroprotection, is released by neurons and the receptor is expressed by microglia, their interactions constituting a neuron-microglial signaling system (Ransohoff and El Khoury, 2015). The fractalkine expressed by neurons can induce adenosine release from microglia. This adenosine (via adenosine A1 receptor) can activate survival pathways in neurons sensitive to excitotoxicity challenge (Lauro et al., 2008, 2010). The signaling mediated by CX3CR1 could regulate microglial behavior in the neurodegenerative diseases.

The presence of protein aggregates in the CNS is a common feature of most neurodegenerative disorders. These aggregates are identified by the Toll-like receptors (TLRs) which are danger-signal sensors. Microglial cells express these receptors (TLR1-TLR9) and their co-receptors, which promote microglial activation (Gonzalez et al., 2014). Concretely, TLR4 and TLR2 are associated with both neuro-inflammation and clearance of protein aggregates in neurodegenerative disorders (Jack et al., 2005).

Microglia constitute the first line of immune defense in CNS. After injury these cells become activated and in this state change their morphology, proliferate, migrate to the damage sites, modify the expression of enzymes and receptors, and release a variety of inflammatory factors, such as NO, tumor necrosis factor (TNF-α), interleukin (IL-6) among others (Magni et al., 2012). The morphology of activated microglia includes a retraction of processes, enlargement of the soma, and increased expression of myeloid cell markers (Ransohoff and Cardona, 2010). In their state of high activation, microglial cells acquire an amoeboid morphology and act like macrophages, engulfing debris (Brown and Neher, 2014). Excessive microglia activation might prompt the release of cytotoxic factors, causing neuronal damage, which could accelerate the progression of some CNS diseases.

Microglial cells may undergo two different kinds of activation in response to infections or injuries. The first is a neurotoxic phenotype called M1-like. This phenotype generates a massive inflammatory response releasing interleukin-1β (IL-1β), IL-12, TNF-α and inducible nitric oxide synthase (iNOS). M1 microglial cells present amoeboid morphology as well as high phagocytic capacity and motility (Varnum and Ikezu, 2012; Gonzalez et al., 2014; Jones and Bouvier, 2014). However, in certain circumstances, the neuroinflammation can help stimulate myelin repair or remove toxic aggregated proteins and cell debris from CNS (Ding et al., 2004; Simard et al., 2006; Glezer et al., 2007). After this acute M1 activation, microglial cells can suffer an uncontrolled activation leading to a state of chronic inflammation. In this state, microglia release neurotoxic inflammatory factors (TNF-α, IL-1α, IL-1β, IL-6, NO, hydrogen peroxide, superoxide anion, chemokines, and glutamate), which lead to neuronal death (Block et al., 2007; Lull and Block, 2010; Burguillos et al., 2011; Kettenmann et al., 2011; Gordon et al., 2012).

The second microglial phenotype, M2-like, secrete anti-inflammatory mediators and neurotrophic factors, thus inducing a supportive microenvironment for neurons (Kettenmann et al., 2011). The M2 microglial cells are characterized by thin cellular bodies and ramified processes (Menzies et al., 2010; Komori et al., 2011; Varnum and Ikezu, 2012; Jones and Bouvier, 2014; Zhou et al., 2014). These cells can release anti-inflammatory cytokines including IL-4, IL-13, IL-10, TGF-β and neurotrophic factors, such as insulin-like growth factor 1 (IGF-1) to assist inflammation resolution and promote neuron survival (Suh et al., 2013; Tang and Le, 2016). M2 microglia are the major effector cells with the potential to dampen pro-inflammatory immune responses and promote the expression of repair genes (Tang and Le, 2016). The change of microglia between M1 and M2 phenotypes is a dynamic process and microglial activation can switch from M2 to M1 phenotype during the course of disease (Cherry et al., 2014).

Recently, it has been reported that microglia release extracellular microvesicles (Evs) by exocytosis. These microvesicles are involved in all immune activities and can be protective or detrimental, affecting some pathologies of the CNS. EVs have a heterogeneous molecular composition, including receptors, integrins and cytokines, bioactive lipids, miRNA, mRNA, DNA, and organelles, being similar to their parental cells. They can be detected in the plasma and other biological fluids such as the cerebral spinal fluid (CSF). The microglial EVs representing a “liquid biopsy” of their parental cells, and could provide information on the functional phenotype (protective or damaging) of microglial cells over the course of neurodegeneration (Nigro et al., 2016).

Microglia and astrocytes are the main innate immune effector cells in the CNS (da Fonseca et al., 2014). Under pathological conditions, astrocytes and microglia can collaborate to induce an inflammatory response. After injury, astrocytes produce cytokines and chemokines (CCL2, CXCL1, CXCL10, GM-CSF, and IL-6), which activate microglia and recruit peripheral immune cells to the CNS. By contrast, a recent report has described an astrocyte subtype A1 that is abundant in AD and PD and other human neurodegenerative diseases. Activated microglia can induce A1 astrocytes by secreting IL-1α, TNF, and C1q, and this type of astrocyte contribute to the death of neurons in the neurodegenerative disorders and could be analog to the M1-like phenotype microglia (Liddelow et al., 2017).

Microglia, together with endothelial cells, pericytes, and astrocytes, form the functional blood-brain barrier (BBB) that selectively separates the brain parenchyma from blood circulation. In this perivascular location, the microglia survey the influx of blood-borne components entering the CNS. The activated microglia can induce the dysfunction of the BBB, being correlated with the disruption of the BBB in the neurodegenerative diseases (Dudvarski Stankovic et al., 2016). During inflammatory conditions, innate immune cells (DCs, neutrophils, monocytes, and natural killer cells) and adaptive immune cells (activated B cells together with CD4+ and CD8+ T cells) are recruited by chemoattractants to cross the BBB from the periphery. The presence of this cellular infiltrate in the CNS can directly or indirectly provoke neuroinflammation by producing pro-inflammatory cytokines/chemokines. All this could generate oxidative stress, which leads to neuronal death. In addition, activated microglia are capable of upregulating CD11c, MHC I, and MHC II to act as antigen-presenting cells, which activate T cells. This activation would in turn damage the nervous system (Xu et al., 2016).

As mentioned above, during the inflammatory process, there is a are released of cytokines. Cytokines bind to receptors in the microglia and activate the JAK/STAT signaling pathway (Yan et al., 2016). This pathway plays a critical role in the initiation and regulation of innate immune responses and adaptive immunity (Yan et al., 2016). Although the same JAK/STAT components are used, the gene expression in response to a specific cytokine, depending on the cell type (van Boxel-Dezaire et al., 2006). This pathway constitutes a pattern-recognition system by which microglial cells respond to foreign antigens and inflammation in the CNS (Hanisch and Kettenmann, 2007).

In microglial cells, other receptors called the “triggering-receptors-expressed-on-myeloid-cells” (TREM) are thought to play a central role in the immune-system regulation and inflammation. The signaling pathway TREM2 regulates apoptosis, the immune response, and phagocytic activity. Brain homeostasis without inflammation depends on eliminating extracellular aggregates and apoptotic debris, this being mediated by the TREM2/DAP12 receptor complex (Han et al., 2017). The signaling pathway TREM2 regulates the apoptosis, the immune response, and the phagocytic activity. This pathway, induced in the microglial cells by anti-inflammatory cytokines, is modulated by CD33 and is down-regulated by agonists of TLR2, 4, and 9, as well as by inflammatory stimuli such as lipopolysaccharides and RNA interference. An overexpression of TREM2 promotes phagocytosis and reduces the pro-inflammatory response (Han et al., 2017). This receptor is a critical regulator of microglia and macrophage phenotype and is involved in neurodegenerative diseases (Andreasson et al., 2016).

After damage, microglia transform into active phagocytes. These cells migrate to the damaged area and adopt an amoeboid morphology, releasing both pro- and anti-inflammatory molecules. They also have the capacity to remove apoptotic cells and debris. As mentioned above, for phagocytosis to occur the expression of specific receptors on the microglial surface is necessary. The principal receptors are the TLRs, which have high affinity for pathogens, and TREM2, which recognizes apoptotic cellular substances (Hsieh et al., 2009). In addition, other receptors also participate in cell-debris clearance (Fc receptors, complement receptors, scavenger receptors (SR), pyrimidinergic receptors P2Y, G-protein coupled,6 (P2RY6), macrophage antigen complex 2 (MAC-2), mannose receptor, and low-density lipoprotein receptor-related protein (LRP) (Fu et al., 2014).

Although microglia are the main agents responsible for phagocytosis of cell debris in the CNS, the complement system can play a primordial role in removing damaged and apoptotic cells (Fakhoury, 2016). Microglial cells can activate the complement by local secretion of the complement component from both the classical and the alternative pathway and also express C3 and C5 (Luo et al., 2011). The complement also participates in the physiological process, termed synaptic pruning. The synapses and axons have to be labeled by complement components C1q and C3 before being phagocytosed, which prompts their selective recognition by microglial cells (Paolicelli et al., 2011; Linnartz et al., 2012; Schafer et al., 2012).

Given the central role of microglial cells in neurodegeneration, the evaluation of activated microglia in vivo is an important approach. Positron emission tomography (PET) is the most widely used in vivo method for detecting microglial activation (Owen and Matthews, 2011; Mirzaei et al., 2016). It has been found that activated microglia and astrocytes overexpress mitochondrial translocator protein (TSPO) within or surrounding senile plaques. Thus, it has been proposed that neuroimaging of TSPO using PET is a good marker of neuroinflammation (Cosenza-Nashat et al., 2009; Pasqualetti et al., 2015).

The primary pathogenic process in AD is the accumulation of Aβ protein. This protein aggregates into extracellular amyloid plaques, which are the hallmark of this pathology (Southam et al., 2016). The amyloid hypothesis for AD is based on a linear, quantitative, centered neuron model. This model postulates that the initial deposition of Aβ triggers mechanisms that progressively lead to Tau pathology, synaptic dysfunction, inflammation, neuronal loss and finally to dementia (De Strooper and Karran, 2016). Recently, evidence has been reported that Aβ protein acts by increasing tau pathology through the formation of tau species capable of producing new aggregates (Bennett et al., 2017).

After acute inflammatory damage, the brain glial cells respond to repair the tissue. If the stimulus persists, it produces an inflammatory chronic state that leads to neuronal dysfunction, injury, and loss (Streit et al., 2004; Calsolaro and Edison, 2016). As mentioned before, inflammation is one of the possible causes in the development of AD (Wyss-Coray, 2006). The increase in Aβ deposition induces the activation of astrocytes as well as microglia (Cagnin et al., 2001). These activated cells can release both pro- and anti-inflammatory mediators, leading to a state of chronic inflammation in the tissue. This inflammation not only occurs in response to Aβ deposition, but is also capable of generating, via feedback mechanisms, more Aβ while weakening the mechanisms responsible for its elimination (Parpura et al., 2012).

The Soluble Aβ oligomers and Aβ fibrils can react to various receptors expressed by microglia, including CD14, CD36, CD47, α6β1 integrin, class A scavenger receptor, receptor for advanced glycosylation end products (RAGE) and TLRs (Stewart et al., 2010). The RAGE is an important cell-surface receptor for Aβ in the endothelial cells, neurons, and microglia, and increased expression in these cell types has been demonstrated in AD (Yan et al., 1996). The interaction of Aβ with RAGE causes oxidative stress in neurons, enhances inflammatory responses in microglia, and is involved in reversed transport of Aβ across the BBB in endothelial cells (Deane et al., 2012). The binding of Aβ to CD36 (cell surface microglial co-receptor) promotes the TLR4 and/or TLR6 phosphorylation and activation, resulting in the production of inflammatory cytokines and chemokines (Stewart et al., 2010).

Recently, an alternative pathway has been described for intracellular signaling produced by the binding of Aβ to microglial cells, activating NLRP3 inflammasome (Heneka et al., 2013; Sheedy et al., 2013). NLRP3 inflammasome is an intracellular protein complex. Their assembly and activation regulates activation of caspase-1, which catalyzes the cleavage and activation of proinflammatory cytokines of the IL-1β family, promoting the secretion of these, now biologically active, cytokines. These cytokines could induce neuronal degeneration (Gold and El Khoury, 2015). In addition, NLRP3 inflammasome activation reduces phagocytosis of Aβ by microglial cells, thus increasing the Aβ depositions and contributing to the pathogenesis of AD (Garlanda et al., 2013; Gold and El Khoury, 2015).

Microglial cells are important for the normal functioning of neurons in the CNS. They provide trophic support to neurons and regulate synapses. The altered microglial behavior could induce neuronal degeneration in AD (Southam et al., 2016). During development, microglia are involved in synapse elimination and these mechanisms may be aberrantly reactivated in the aged brain, contributing to the synapse loss in AD. The synapse loss in the hippocampus and association cortices is an early hallmark of AD and strongly correlates with cognitive impairment (Hong et al., 2016). In the healthy development of the brain, the proteins of complement participate in synapse pruning. Synapses to be cleared express C3 and binding to CR3 on microglia, resulting in microglial phagocytosis of the synapse (Schafer et al., 2012; Southam et al., 2016). In the healthy adult brain, these complement components are downregulated. However, in aging brains, C1q and C3 are highly upregulated and are deposited on synapses, particularly in the hippocampus, the most vulnerable region in the synapse loss in AD (Bialas and Stevens, 2013). These findings highlight the importance of complement regulation for normal synaptic maintenance (Southam et al., 2016). In addition, it has been shown that Aβ can bind and regulate the expression and localization of complement proteins in the AD brain. An upregulation has been observed in the complement proteins (C1q, C3, and C4) localized in senile plaques also known as neuritic plaques (Hong et al., 2016).

Microglial cells can use additional mechanisms for synapsis regulation. The release of brain-derived neurotrophic factor (BDNF) by microglial cells induces synaptic pruning. However, the depletion of this factor in the microglia results in learning and memory impairment (Parkhurst et al., 2013). The activation of the fractalkine receptor (CX3CR1) in microglial cells, increases synaptic strength. However, deficiency in this receptor results in a reduced hippocampal synaptic plasticity (Rogers et al., 2011; Clark et al., 2015).

It has been reported that in the later stages of AD, there is destruction of axons, dendrites, and synapses, in which microglia has a relevant role (Parpura et al., 2012). In AD brains reactive microglia has been found colocalized with amyloid plaques. In addition, the reactive astrocytes accumulate around senile plaques next to the activated microglia (Heneka et al., 2015). In brain, astrocytes as well as microglia are capable of capturing Aβ for degradation (Pihlaja et al., 2011). In AD patients, astrocytes in the entorhinal cortex accumulate Aβ, this accumulation being positively correlated with the extent of AD (Nagele et al., 2003). Moreover, astrocytes can also induce microglia to perform Aβ phagocytosis by regulating the release of the apo E and the ATP-binding cassette (ABCA) protein. Studies in vitro have demonstrated that microglial phagocytosis of Aβ is more effective in the presence of supernatants derived from astrocytes (Terwel et al., 2011). In AD, mutations in ABCA7 can cause a loss of receptor activity, resulting in reduced microglia phagocytic function (Southam et al., 2016).

Microglial senescence can enhance the sensitivity of microglia to inflammatory stimuli; this phenomenon is called “priming” (Heneka et al., 2015). In addition, aged microglia show reduced phagocytic capacity. This process could be due partly to a reduction in the ability of microglia to recognize phagocytic targets (Udeochu et al., 2016). Both inflammation and reduced microglial phagocytic capacity in AD can contribute to the decline in synaptic plasticity observed in this pathology (Ritzel et al., 2015; Udeochu et al., 2016).

In AD, protein aggregation is caused by declining of protein homeostasis (proteostasis) (Mosher and Wyss-Coray, 2014). As mentioned above, Aβ deposits can attract and activate microglia. Presumably, microglial proliferation around plaques could serve as a line of defense to limit the deposition of amyloid. Nonetheless, it seems that microglial cells clustered around Aβ− deposits have become incapable of removing the amyloid (Calsolaro and Edison, 2016). The sustained exposure to cytokines, chemokines and Aβ, could be responsible for the functional impairment of microglial cells located around Aβ− deposits (Heneka et al., 2015). In addition, microglial-specific genetic alterations may be related to this microglial dysfunction. The expression of beclin 1, a protein associated with autophagy pathway, is reduced in the brain of patients with AD, leading to disruption in phagocytosis and retromer-mediated recycling of the phagocytic receptors CD36 and TREM2 in microglia (Mosher and Wyss-Coray, 2014).

Similarly, mutations in TREM2 can trigger the loss of phagocytic capacity in microglial cells. TREM2 inhibits pro-inflammatory cytokine production, facilitates phagocytosis and promotes cell survival. Thus, TREM2 dysfunction could induce the loss of the homeostasis in the tissue (Painter et al., 2015). Missense mutations in TREM2 lead to a significant risk of developing AD (Jonsson et al., 2013; Meyer-Luehmann and Prinz, 2015).

As mentioned above, in AD the Aβ peptide that is aggregated extracellularly in the neuritic plaques produces an inflammatory environment and a chronic activation of microglial and astroglial cells (D'Andrea, 2005). Activated microglia can shed MVs in response to several signals, including cytokines. These MVs contain bioactive molecules (i.e., IL-1β, proteases, and MHC-II) which modulate the activity of neuronal and non-neuronal cells (Antonucci et al., 2012). In AD patients, the production of MVs is very high, reflecting microgliosis. These extracellular vesicles can be isolated form cerebrospinal fluid (Guerriero et al., 2016).

In patients with AD, an upregulation of iNOS has been found. In the course of AD, cytokines stimulate iNOS in microglia and astrocytes, generating high NO levels (Vodovotz et al., 1996). NO can interact with signaling cascades and regulate gene transcription, impair mitochondrial respiration or directly induce neuron death by apoptosis or necrosis (Parpura et al., 2012). In addition, the NO can promote the nitration of Aβ, increasing their propensity to aggregate (Kummer et al., 2011; Heneka et al., 2015).

In late-onset Alzheimer's disease (LOAD), accumulating Aβ and NO harm the cells of the cerebral vessel, causing the onset of cerebral amyloid angiopathy (Nelson et al., 2016). The neurovascular unit, constituted by cerebral blood vessels, perivascular glia and neurons, are associated with distinct inflammatory, functional, and morphological alterations in AD (Heneka et al., 2015). In LOAD, damaged blood vessels can hinder neurogenesis from neural stem cells in the subventricular zone and hippocampus, preventing the processing and storage of new memories (Licht and Keshet, 2015; Chiarini et al., 2016).

Recently, it has been suggested that the involvement of glial cells in AD is related with the transient receptor potential melastatin member 2 (TRPM2). This receptor, besides regulating synaptic plasticity and glial cell activation, also modulates oxidative stress and inflammation (Yuruker et al., 2015). TRPM2 channel can be activated by Aβ. The activation of these channels in microglia and astrocytes leads to Ca²⁺ overload and subsequent inflammation and oxidative stress. All of this causes mitochondrial dysfunction, [Ca²⁺]_I increase, Aβ accumulation, glutamate-receptor dysfunction, and finally plasticity alterations and dementia (Yuruker et al., 2015; Wang et al., 2016).

PD is characterized by α-synuclein (α-syn) accumulation, dopaminergic neuron loss and inflammation (Beach et al., 2014; Wang et al., 2015). The pathological hallmark of this disorder is the presence of Lewy bodies. The Braak hypothesis has suggested that PD begins in the olfactory bulb or the gastrointestinal tract. These areas are constantly exposed to the environment, and in them, the Lewy bodies accumulate (Kannarkat et al., 2013). Lewy bodies are constituted mainly by misfolded α-syn and other intraneuronal protein aggregates such as tau and ubiquitin proteins (Campello et al., 2013; George and Brundin, 2015). The nitration, phosphorylation, and ubiquitination of α-syn can promote their pathological accumulation, inducing neurodegeneration (Giasson et al., 2000; Tofaris et al., 2003; Anderson et al., 2006). In addition, missense mutations in α-syn can produce the protein aggregation in familial PD (Conway et al., 1998).

Reportedly, α-syn can induce microglial activation, which in turn can promote α-syn phagocytosis (Cao et al., 2012) and neuroinflammation. The neuroinflammation leads to the loss of dopaminergic neurons and drives the chronic progression of neurodegeneration in PD (Schapansky et al., 2015). Accumulations of activated microglia have been found around dopaminergic neurons in postmortem human brains (Hamza et al., 2010). Microglial cells can be activated by α-syn, via TLRs, initiating an immune response (Fellner et al., 2013). Specifically, the stimulation of TRL2 and TRL4 in the microglia induces signaling cascades involved in the inflammatory response. It has been shown in PD patients that TLR2 colocalized with CD68+ amoeboid microglia indicates microglial activation at the sites of neuronal loss (Doorn et al., 2014). Also, TRL4 can induce microglial phagocytosis of α-syn. Deficiencies in this receptor can prompt poor α-syn clearance and neurodegeneration (Fellner et al., 2013).

The clearance of α-syn also can be promoted by the leucine-rich repeat kinase 2 (LRRK2) gene. This gene has been proposed as a regulator of the microglial response (Schapansky et al., 2015). LRRK2 is the most commonly mutated gene in both idiopathic and familial PD. Pathogenic mutations in LRRK2 influence the ability of microglia to internalize and degrade α-syn, exacerbating α-syn-induced microglial pathology, and neuroinflammation (Schapansky et al., 2015). In addition, other genes whose mutations are responsible for rare familial forms of PD have been identified, including, SNCA, PARKIN, DJ-1, and PINK1 (Chao et al., 2014).

Persistent microglial activation is known to exert harmful effects that result in dopaminergic neuron death. One of the most important signaling pathways associated with the microglial activation in PD involves nuclear factor-kappa B (NF-kB) (Zhang et al., 2017). The activation of this factor could increase the release of proinflammatory cytokines such TNF-α and interleukin 1β by microglial cells (Mogi et al., 1996; McLaughlin et al., 2006). In addition, proinflammatory mediators such as TNF-α, IL-1β, and IFN-γ have been found at higher levels in the midbrain of PD patients (Wang et al., 2015). Immunomodulators, including the CX3CL1, CD200, CD22, CD47, CD95, and neural cell adhesion molecule, sustain the rest state of microglia under normal conditions (Chang et al., 2000; Sheridan and Murphy, 2013). In rat PD models, both deficiency CX3CL1 or CX3CR1 as well as the dysfunction of CD200-CD200R signaling have been shown to increase microglial activation and the degeneration of DA neurons (Wang et al., 2011; Zhang et al., 2011).

The cytokines released by activated microglia can attract peripheral immune cells (e.g., CD4 T-cell) to the brain. In vivo and in vitro studies have demonstrated that overexpression of α-syn can induce the MHC-II expression by microglia. The MHC-II expression in microglia cells can play an important role in the immune responses (innate and adaptive) in PD (Michelucci et al., 2009; Harms et al., 2013; Gonzalez et al., 2015).

In addition, dopaminergic neurons seem to be especially sensitive to several factors that can induce cell damage and eventually cell death. It has been suggested that mitochondrial malfunction leads to reduced energy metabolism and induces neuroinflammation via NO and ROS production, which ultimately entails neurodegeneration (Vivekanantham et al., 2015). The production of NO and superoxide exerted by activated microglia in PD can cause the degeneration of dopaminergic neurons (Appel et al., 2010). The high cytosolic concentrations of free DA can produce oxidative stress and can interact with α-syn, promoting the neurodegenerative process (Mosharov et al., 2006). In addition, the neuromelanin (dark, complex endogenous polymer derived from DA) can activate microglial cells, inducing neuroinflammation and neurodegeneration of dopaminergic neurons in PD (Zecca et al., 2008; Herrera et al., 2015).

Neuroinflammation is produced by the set of integrated responses of all the CNS immune cells including microglia, astrocytes and infiltrating T-lymphocytes (Le et al., 2016). Gliosis in the PD is an atypical activation where astrogliosis is largely absent while the microglia is highly activated by the disease. The low astroglial response may be caused by degeneration due to an increase of α-syn in the astrocyte (Stefanova et al., 2001; Orr et al., 2002; Sofroniew and Vinters, 2010). Astrocytes are responsible for secreting glutathione and transporting to neurons in response to neural excitatory stimuli. A lower level of glutathione has been detected in the CNS of PD patients, and thus the antioxidant capacity in the tissue could be impaired, probably secondary to the astroglial defect (Olanow and Tatton, 1999).

Recently, the kinurenic pathway (KP) has been implicated in the inflammatory and neurotoxic processes in PD. Astrocytes produce a neuroactive component of KP, kynurenic acid, considered to be neuroprotective. By contrast, quinolinic acid, released by microglia, can activate the NMDA receptor-signaling pathway, leading to excitotoxicity and increasing the inflammatory response. Based on this, KP may represent an important target to prevent the progression of the underlying neurodegeneration observed in PD (Lim C. K. et al., 2017).

Nowdays, it has been reported that prothrombin kringle-2 (pKr-2), which is a domain of prothrombin (which is produced by active thrombin), could be involved in PD. Also, pKr-2 induced DA neuronal death in an experimental PD model (Kim et al., 2010). In addition, in PD patient's pKr-2 expression is significantly increased and co-localized in activated microglial in the substantia nigra, leading to disruption of the nigrostriatal DA projection. This disruption could be mediated through the neurotoxic inflammatory events brought about by the pKr-2 upregulation, wich trigger microglial activation via TLR4. On the basic of these results, limiting pKr-2-induced microglial activation may be an effective therapeutic strategy for protecting DA neurons (Leem et al., 2016).

AD, PD, and glaucoma are neurodegenerative diseases that share a common pathogenic mechanism, in which the neuroinflammation, in the form of microglial activation, plays an important part. The differential activation of microglia (M1 or M2 phenotypes) can produce a neurotoxic or neuroprotective environment, and could constitute a key in neuroinflammation regulation. In the search for a new strategy to control neuroinflammation, it might be more effective to change the M1 phenotype to the M2 phenotype than to block microglial activation completely. In the regulation of microglial activation, several cell types including, neurons, astrocytes, and T-cells are involved. When the neuroinflammatory process is triggered by protein aggregates (Aß, α-syn, pTau etc.), peripheral immune cells infiltrate CNS and prompt more activation on resident microglia, favoring neuroinflammatory processes.

Neuroinflammatory processes occur not only in the brain but also in the retina, because the retina is a projection of the CNS. Thus AD, PD, and glaucoma share neuroinflammatory changes in the retinal tissue. The follow up of neuroinflammatory processes in the retinal tissue may be useful for the early diagnosis and monitoring of neurodegenerative diseases. Future research could therefore address these issues to provide fuller knowledge of neuroinflammatory events that occur in AD, PD, and glaucoma, especially the contribution of microglia. This might help in the development of new therapeutic strategies to control neuroinflammation and thereby spur progress in treating these neurodegenerative diseases.

Conception of the work: Rd, JS, AR, ES, BR, AT, and JR. Acquisition, analysis and interpretation of data for the work: Rd, JS, AR, ES, and JR. Bibliographic research: Rd, JS, AR, ES, DA, PR, IL, and JR. Drafting the work: Rd, JS, AR, ES, DA, IL, and JR. Revising critically for important intellectual content: Rd, JS, AR, ES, DA, IL, PR, BR, AT, and JR. Final approval of the version to be published Rd, JS, AR, ES, IL, DA, PR, BR, AT, and JR. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Rd, JS, AR, ES, DA, IL, PR, BR, AT, and JR.