Glial cell dysregulation : a new perspective on Alzheimer disease

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(1)Neurotoxicity Research, 2007, VOL. 12(4). pp. 215-232. F.P. Graham Publishing Co.. Glial Cell Dysregulation: a New Perspective on Alzheimer Disease ROMMY VON BERNHARDI. *. Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile. Marcoleta 391, Santiago, Chile. rvonb@med.puc.cl. (Submitted 02 May 2007; Revised 01 August 2007; In final form 01 August 2007). Alzheimer disease (AD) is a major cause of dementia. Several mechanisms have been postulated to explain its pathogenesis, beta-amyloid (Aβ toxicity, cholinergic dysfunction, Tau hyperphosphorylation, oxidative damage, synaptic dysfunction and inflammation secondary to senile plaques, among others. Glial cells are the major producers of inflammatory mediators, and cytotoxic activation of glial cells is linked to several neurodegenerative diseases; however, whether inflammation is a consequence or the cause of neurodegeneration is still unclear. I propose that inflammation and cellular stress associated with aging are key events in the development of AD through the induction of glial dysfunction. Dysregulated inflammatory response can elicit glial cell activation by compounds which are normally poorly reactive. Inflammation can also be the major cause of defective handling of Aβ and the amyloid precursor protein (APP). Here I review evidence that support the proposal that dysfunctional glia and the resulting neuroinflammation can explain many features of AD. Evidence supports the notion that damage caused by inflammation is not only a primary cause of neurodegeneration but also an inducer for the accumulation of Aβ in AD. Dysfunctional glia can result in impaired neuronal function in AD, as well as in many progressive neurodegenerative disorders. We show. that microglial cell activation is enhanced under pro-inflammatory conditions, indicating that glial cell responses to Aβ related proteins can be critically dependent on the priming of glial cells by pro-inflammatory factors. Keywords: Microglia; Alzheimer disease; β−Amyloid; Inflammation; Neurodegeneration. INTRODUCTION Alzheimer disease (AD) is the most common form of dementia in old age. It is not a unique nosological entity, as considerable heterogeneity exists in its risk factors, pathogenesis and neuropathological findings. Its neuropathology includes neuronal loss in the hippocampus, entorhinal and temporoparietal cortex (Uylings and de Brabander, 2002). It is characterized by two lesions, amyloid plaques constituted by the deposition of extracellular fibrillar beta-amyloid (Aβ) aggregates, and intracellular neurofibrillary tangles (Selkoe, 1996). Both are closely associated with activated microglia and astrocytes (Sheng et al., 1995). It is unresolved if Aβ aggregation is the cause of AD or just a consequence of other pathophysiological changes such as a pro-inflammatory environment. Aβ accumulation does not necessarily constitute a senile plaque. Non-demented aged persons have diffuse Aβ aggregates which lack inflammatory response (Dickson,. *Corresponding author: Tel.: 56-2-354 6936; FAX: 56-2-632 1924; E-mail: rvonb@med.puc.cl ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2007 FP Graham Publishing Co., www.NeurotoxicityResearch.com.

(2) 216. R. VON BERNHARDI. 1997; Duyckaerts et al., 1998), suggesting that Aβ deposition could be a consequence of aging but requires additional factors to become pathologic. Aβ originates from the proteolytic processing of APP. Under non-pathological conditions, most APP is processed by a protease named α-secretase. In contrast, Aβ is produced by the sequential action of two proteases, β-secretase and γ-secretase (Haass, 2004). Mutations of genes for APP and presenilins (PS1 and PS2) lead to increased production of Aβ (Selkoe, 2000). These mutations associate with the familial forms of AD, accounting for 3-5% of AD patients. However, differences in the clinical progression and especially in the age of onset (2 or even 3 decades earlier for familial AD), have led to the proposal that they are two different pathologies. The presence of the Apolipoprotein E4 (apoE4) allele, implicated in the clearance of Aβ is an important risk factor in developing sporadic AD (Roses, 1996; Farrer et al., 1997). Also gene polymorphisms for cytokines IL-6, IL-1α and transforming growth factor-β1 (TGF-β1) affect the initial age and the progression of the disease (Papassotiropoulos et al., 1999; Kolsch et al., 2001). Although strong, this evidence for the association of inflammation is still circumstantial since we have not demonstrated that inflammation causes the development of plaques. Furthermore, different studies show little overlap in the reported changes, failing to provide a strong definitive correlation between inflammation and the risk of developing AD. The way Aβ induces damage is still a matter of debate. Aβ is toxic for neurons and glial cells in vitro (Walsh et al., 1999; Ramírez et al., 2005; Roth et al., 2005) and in vivo (see Harkany et al., 2000). Aβ neurotoxicity can be direct (Pike et al., 1991; Geula et al., 1998; Lambert, 1998) or indirect through glial cell activation (Meda et al., 1995; Ishii et al., 2000, von Bernhardi and Eugenín, 2004). It has also been proposed that Aβ induces release of excitatory neurotransmitters like glutamate (Canevari et al., 2004), increasing intracellular calcium and the production of reactive oxygen species (ROS). Aβ can also have a role in synaptic pathology (Kamenetz et al., 2003; Gylys et al., 2004; Takahashi et al., 2004). Functional alterations of hippocampal synapses can be observed prior to either neuronal degeneration or amyloid. plaque formation (Selkoe, 2002). There is also a reported deficit in long-term potentiation (LTP) in aged rats. This attenuation has been associated with microglial activation and inflammatory cytokine production (Griffin et al., 2006). On the other hand, APP transgenic mice also evidence synaptic dysfunction prior to morphological changes (Palop et al., 2003; Westphalen et al., 2003) or Aβ deposition (Chapman et al., 1999). There is evidence that synaptic dysfunction is caused by soluble oligomeric assemblies of Aβ (Selkoe, 2001; Walsh et al., 2002; Kayed et al., 2003). However, deficits in cognitive and synaptic function (including attenuation in LTP) have been also reported as a consequence of increased concentration of inflammatory cytokines, such as IL-1β (Murray and Lynch, 1998). Because the studies evaluating the effect of Aβ on synaptic function did not address its possible induction of an inflammatory response, this alternative explanation has not been overruled. Studies on APP transgenic mice further suggest that Aβ accumulation is not enough to explain AD. The transgenic mice develop plaques, but they do not develop significant neurodegeneration. They show memory impairment and synaptic dysfunction associated to the presence of plaques, although the relationship of these findings with AD, in which there are clearly neurodegenerative changes is not clear. Immunotherapy in APP over-expressing mice (Schenk et al., 1999) prevents the formation of amyloid plaques, neuronal dysfunction and glial reactivity associated to increased uptake of Aβ by microglia, and results in improved cognition (Younkin, 2001). The results are consistent with microglia having a key protective role, suggesting that, far from being detrimental, microglial activation can reduce AD pathology. Here I will review evidence that support the notion that glial dysfunction associated to the pro-inflammatory environment of the aging brain can be a pathogenic factor for AD. GLIAL DYSREGULATION HYPOTHESIS IN AD The cellular mechanisms involved in the development of AD are complex in nature and extend beyond amyloid plaques and neurofibrillary tangles. Aging of the CNS associates with a pro-in-.

(3) GLIAL CELL DYSREGULATION & ALZHEIMER DISEASE. 217. FIGURE 1 Pathogenesis of Alzheimer's disease - The dysfunctional glia hypothesis: Several different pathophysiological events contribute to neurodegeneration in Alzheimer's disease. Inflammation, either secondary to aging, to various stimuli or injury, can be responsible for abnormal glial activation, increased production of Aβ and neuronal dysfunction. At late stages, it is also directly or indirectly involved in the induction of neurodegeneration. Glial activation results in the release of various cytokines and the generation of reactive species, contributing to the inflammatory process. The increased expression of Aβ results in further neuroinflammation, perpetuating glial activation, synaptic dysfunction and cell damage. Inflammatory mediators, neurodegenerative processes and the proposed trophic effect of APP and Aβ could also affect neuronal function and regulation, resulting in cognitive alteration and further impairing their capacity of modulation of glial activation.. flammatory status inducing functional changes on microglia and astrocytes. These changes represent a shift in basal cell reactivity of defense responses that can lead to regulatory impairment and favor progression of neurodegenerative processes. I propose that Aβ accumulation is a consequence and not the cause on AD pathogenesis. The "inflammation hypothesis" stresses that hyperactive microglia are the primary cause of AD-associated neurotoxicity. In contrast, I propose that AD is not caused by hyperactive but rather dysfunctional microglia (FIG. 1). Active microglial cells are needed as scavenger cells in the CNS. However, by not responding to normal regulatory feedback mechanisms and/or having an impairment in their ability to clear Aβ. (Paresce et al., 1997), microglial cells lose their ability to handle potentially toxic compounds and become cytotoxic because of persistent inflammatory activation. Other changes relevant to AD also could depend on aging. Oxidative stress and the generation of free radicals promote amyloidogenic processing of APP. Transient hypoxia can lead to mitochondrial dysfunction, resulting in oxidative stress, impairment of membrane integrity and amyloidogenic APP cleavage with a pattern similar to that observed in sporadic AD (Chen et al., 2003). A state of increased inflammatory reactivity potentiates the response of glial cells and can result in an overreaction of microglia when exposed to a condition that.

(4) 218. R. VON BERNHARDI. normally would fail to induce their activation such as APP or Aβ, compounds that are not potent activators by themselves (von Bernhardi and Eugenín., 2004; von Bernhardi et al., 2007). Abnormal glial activation can also impair the capacity of glia to uptake and degrade Aβ (Rogers et al., 2002). Impairment of uptake or degradation allows Aβ accumulation even in the absence of changes of Aβ production. The persistence of Aβ can establish a vicious circle, further potentiating an inflammatory reaction. In time, chronically or multiple-event activated microglia and astrocytes would become neurotoxic by the release of inflammatory cytokines, proteolytic enzymes, complement factors and reactive intermediaries. Regulation of glial activation can be impaired under sustained pro-inflammatory conditions as those reported in the aged brain. We have reported that activation of glial cells by Aβ is low, but it is markedly amplified by the inflammatory priming of glial cells. Also, microglial reactivity to Aβ is attenuated by the presence of astrocytes. However, attenuation is not observed when glial cells are exposed to pro-inflammatory factors (von Bernhardi and Eugenín, 2004). The inflammatory priming of glial cells, rather than Aβ aggregates, could be the principal trigger for glial activation and inflammation in AD. We propose that in the brain, under physiological conditions the microglial reaction to Aβ would be mild and down regulated by the activation of astrocytes. However, under pro-inflammatory conditions, down regulation by astrocytes could fail, thus enhancing microglial activation. This in turn can increase cytotoxicity and Aβ aggregation, establishing a vicious circle. Increased Aβ can become a stimulus for the activation of glial cells also in familial AD, triggering an inflammatory response. In these patients, whereas dementia occurs at younger ages, neuropathological lesions become more abundant as the patient ages, suggesting that the association to aging is maintained. Increased TGF-β1 production in response to proinflammatory conditions (Ramírez et al., 2005) is one of the regulatory mechanisms secondary to cell activation (Herrera-Molina and von Bernhardi, 2005), limiting the temporal and spatial extent of the inflammatory response. TGF-β1 deactivates microglial cells and abolishes neurotoxicity (Eyüpoglu et al., 2003). Its modulatory effect. involves activation of Smad3 pathway, which is down regulated in AD patients (Colangelo et al., 2002) and the activation of MAPK- ERK pathways (Saud et al., 2005), which also appear to be neuroprotective (Zhu et al., 2002; 2004a). Dynamic regulation of Smad, PI3K and MAPK pathways, which are associated to TGF-β activity as well as to other inflammatory cytokines, can be key elements for cellular integrity and handling of inflammation. Disappearance or reduction of Smad3, a major effector pathway for anti-inflammatory modulation will modify the regulation and feedback signals resulting from inflammation. There is abundant evidence supporting our hypothesis that glial dysregulation leads to cytotoxicity and the neurodegenerative process characteristic of AD. Identification of the receptor(s) mediating and regulating microglial activation and understanding the molecular mechanisms activated by these receptors are needed to generate better ways to treat neurodegenerative diseases. Here I will discuss data regarding aging-associated changes, inflammation and glial activation by Aβ that are relevant for our understanding of the pathogenesis of AD. CHANGES OF BRAIN MICROENVIRONMENT DURING AGING AND AD Aging is the strongest risk factor for AD, rising AD prevalence to 25-35% for people over 85 years old (Kukull and Bowen, 2002). Autopsy studies show a high incidence of neuropathological lesions and reveal that AD often occurs in conjunction with other pathologic lesions, especially vascular dementia and dementia with Lewy bodies (Fu et al., 2004). The overlap reveals the existence of common pathophysiological mechanisms, such as glial cell activation and up regulation of inflammatory mediators. By using transgenic mice expressing enhanced-green fluorescent protein under a promoter specific for macrophage cells, Sierra et al. (2007) were able to show that microglial cells increased mRNA expression of several cytokines, while they preserved their ability to respond to inflammatory challenge with LPS. Those results imply that inflammatory machinery in aging microglia is functional, whereas they also imply that the.

(5) GLIAL CELL DYSREGULATION & ALZHEIMER DISEASE. end result is a stronger inflammatory response than that observed in young individuals. Mild morphological alterations and preserved function contrast with the morphological abnormalities described in cognitively normal elders that had previously led to the concept of dystrophic microglia associated to aging (Streit et al., 2004). Increased microglial cells reactivity, cytokine levels, production of nitric oxide (NO) (McCann, 1997) and oxidative stress, by changing the regulation of glial activation, can play a role in aging and more important for our proposal, in the development of neurodegenerative diseases such as AD. Diffuse cortical plaques are frequently observed in non-demented elders (Knopman et al., 2003), but they do not show glial and inflammatory reactivity. Although it is unknown how aging affects the response of microglia to activation-inducing stimuli such as Aβ, there is evidence that microglia from cognitively normal elders secrete several of the cytokines secreted by microglial cells exposed to Aβ (Lue et al., 2001a). Other changes associated with aging can potentiate pathological changes (von Bernhardi, 2005). Brain hypo perfusion (de la Torre, 2002) and small brain infarctions (Vermeer et al., 2003) modify brain parenchyma homeostasis, disrupting energetic metabolism and the maintenance of ionic gradients, increasing intracellular calcium and oxygen radicals. Those changes clearly can contribute to cell regulation impairment. On the other hand, cerebral ischemia induces a strong cerebral inflammatory response (Zhang et al., 1997a), APP expression (Kalaria et al., 1993), and increases in amyloidogenic cleavage of APP (Wen et al., 2004; Yokota et al., 1996). In that sense, besides age-dependent hypo perfusion, the microcirculation in AD patient brains and APP transgenic mice have abnormalities which can further promote ischemia and hypoxia (Zhang et al., 1997b; Farkas et al., 2000). Production of growth factors also declines during aging. Insulin-like growth factor-1 (IGF-1) is required for multiple brain functions, including energy supply, repair, neuron excitability, synaptic plasticity and some cognitive processes (Trejo et al., 2004). The reduction of growth factors contributes to frailty and morbidity. Moreover, lack of IGF-1 is implicated in some of the pathophysiological changes characteristic to AD brains, including. 219. cholinergic dysfunction and neuronal amyloid toxicity. IGF-1 and growth hormone (GH) decreases are partially reversed by donepezil, one of the new cholinesterase-inhibitors (Obermayr et al., 2005). Synaptic function and the ability to generate Long Term Potentiation (LTP) are attenuated in aged rats (Murray and Lynch, 1998), suggesting the existence of changes in neuronal function with age. Besides functional changes, aging monkeys often exhibit cortical neuritic pathology, amyloid plaques and reactive glia associated with senile plaques. However, morphological abnormalities at synapses precede the deposition of Aβ as well as the activation of glia. The response to Aβ also changes with aging. Aβ does not induce damage when injected into young adult rhesus monkey's brain, whereas it causes neuronal loss and microglial reactivity in aged monkeys (Geula et al., 1998). This suggests that changes in older monkeys, through mechanisms still unresolved, can increase the reactivity to Aβ. Because aging also changes the ability of astrocytes to degrade Aβ (Wyss-Coray et al., 2003) and is associated with differences in the oxidative potential of Aβ, we can speculate that in the aged brain, both Aβ accumulation and its potential toxic effect through glial inflammatory activation are potentiated. ROLE OF INFLAMMATION IN AD Inflammation is involved in multiple pathophysiological mechanisms (Lukiw and Bazan, 2000) and the progression of AD (Akiyama et al., 2000; Lim et al., 2000; Neuroinflammation Working group, 2000; McGeer and McGeer, 2001). Inflammation, microglial activation and oxidative stress probably precede the appearance of AD cytopathology (Eikelenboom and van Gool, 2004; Zhu et al., 2004b). Cytokines such as IL-1β and TGF-β and the inducible form of cyclo-oxygenase (COX-2) are elevated in the brain of AD patients (Luterman et al., 2000; Ho et al., 2001). However, those observations fail to establish whether those changes originate the disease or are a compensatory reaction to the degenerative process. Furthermore, it is mandatory to keep in mind that inflammatory mediators are multifunctional and have both pro- and anti-inflammatory effects. Their mere presence does not indicate whether they are beneficial or detrimental..

(6) 220. R. VON BERNHARDI. On the other hand, certain infections (Itzhaki et al., 2004) and neuroinflammation induced by lipopolysaccharide (LPS) (Hauss-Wegrzyniak et al., 1998) increase intracellular accumulation of Aβ (Sheng et al., 2003), inducing neuropathological changes similar to those found in AD brains. It has been proposed that the inflammatory response to Aβ causes the neuronal damage in AD. Epidemiological evidence (Dziedzic et al., 2003; Sala et al., 2003) as well as experimental models of AD (Griffin and Mrak, 2002; Melton et al., 2003) show that pro-inflammatory conditions promote the development of AD. On the contrary, evidence from multiple casecontrol and population-based studies supported a roughly 50% reduction in AD risk after long-term use of non-steroidal anti-inflammatory drugs (NSAID) (Stewart et al., 1997; Broe et al., 2000; Etminan et al., 2003). However, only small trials of indomethacin and diclonefac showed positive effects for AD patients. The lack of success can have several explanations; the timing and dosing of treatment, and the specific NSAID used are some of the possibilities. But also the fact that genetic factors predisposing to inflammatory disease or factors produced in the course of inflammatory disease could explain the lack of effect of anti-inflammatory therapy. Even more, evidence suggests that NSAIDs have COX-independent effects, through various molecular mechanisms, including repression of β-secretase cleaving enzyme 1 (BACE 1), an effect mediated by the activation of PPARγ (Sastre et al., 2006), modulation of γ-secretase activity (Weggen et al., 2001; Eriksen et al., 2003) and inhibition of signal transduction pathways involved in cytokine-mediated inflammation such as NFκB and MAPKs (Tegeder et al., 2001). One of the most interesting NSAID in that respect would be flurbiprofen. Its Aβ-reducing effect appears to be mainly independent of COX activity (Eriksen et al., 2003). Of added interest is the fact that these COX-independent effect and reduction of Aβ in animal models and clinical trials are observed at doses within those used for NSAID treatments. Those recent results suggest that even considering the lack of clear effect of anti-inflammatory therapy, inflammation still can be a relevant mechanism. Evidence also indicates that COX may be the wrong anti-inflammatory target to pursue, being necessary to evaluate other inflammation path-. ways. The cellular bases for neuroinflammation would be reactive microglia and astrocytes. Once again, increased glial activation associated with aging or secondary to proinflammatory stimuli appears as a relevant factor for the participation of glial cells in AD. Activated microglial cells synthesize and release cytotoxic factors including super oxide radicals and NO (Bal-Price and Brown, 2001), inducing apoptotic neuronal death (Wittig et al., 2000). There is lipid peroxidation (Butterfield et al., 2002), protein (Choi et al., 2003) and DNA (Lovell et al., 1999) oxidation in the brain of AD patients. Lipid peroxidation is greater in AD individuals than that found in age-matched controls (Lovell et al., 2001). Several oxidative stress markers are also found in APP transgenic mice (Smith et al., 1998). The expression of iNOS is increased in AD (Luth et al., 2002). Moreover, ROS are also critical for inflammatory gene expression, including iNOS, in glial cells (Pawate et al., 2004). Being microglial cells a robust source of ROS; increased oxidative stress strengthens the participation of microglial dysregulation on AD. IL-1, as well as IL-6 show increased activation in the brains of AD patients (Akiyama et al., 2000). Likewise, activated glial cells surrounding amyloid plaques or exposed to Aβ in vitro secrete pro-inflammatory molecules such as tumor necrosis factor-α, (TNF-α), IL-1β, MCP-1, RANTES (Hu and Van Eldik, 1999) and eicosanoids. Inflammatory molecules secreted by microglia appear to be involved in neurodegenerative mechanisms because they increase sensitivity of neurons to free radicals (Combs et al., 2001), potentiating neurotoxicity. Besides their potential cytotoxic effects, TNF-α and IL-1β can also promote AD by stimulating the synthesis of APP (Goldgaber et al., 1989). A similar effect has been described for TGF-β1 on astrocytes (Rogers et al., 1999). However, the participation of cytokines on amyloidogenesis is not clear. Whereas some results suggest that cytokines stimulate the processing of APP towards the generation of Aβ (Blasko et al., 1999), including the stimulation of β-secretase activity (Sastre et al., 2003), others report that IL-1 and IL-6 have no effect on amyloidosis in APP transgenic mice (see Wyss-Coray, 2006). In contrast, increased expression of TGFβ in APP transgenic mice results in.

(7) GLIAL CELL DYSREGULATION & ALZHEIMER DISEASE. decreased expression of Aβ and amyloid plaque formation in association with microglial and astrocytes activation (Wyss-Coray et al., 2001). On the other hand, inflammation is not necessarily deleterious. TNF-α is neuroprotective against direct metabolic, excitotoxic and oxidative damage, including that induced by Aβ (Cheng et al., 1994; Barger et al., 1995), whereas detrimental effects are described as being associated with gliosis. Those effects led to the proposal that early stages of an inflammatory response can protect neurons (WyssCoray et al., 2002). However, failure to adequately deal with the inciting stimulus results in the subsequent uncontrolled over-activation of microglia, inducing the release of potentially toxic cytokines (Prinz et al., 1999; Hanisch, 2002). CYTOKINES IN THE PATHOGENESIS AND PROGRESSION OF AD Cytokines exert actions in the normal brain, presumably participating in complex behaviors and modulating cell homeostasis, metabolism, synaptic function and plasticity, and neural transmission. Glial cells and also neurons produce inflammatory mediators in response to injury, infection or inflammatory conditions. Inflammatory cytokines are also associated with synaptic regulation. Different effects are often described depending on the concentration of cytokines or other environmental factors. These effects appear to be involved in the pathogenic of various CNS diseases. In light of these observations, we already suggested that early synaptic dysfunction in AD could depend on inflammation, both secondary to aging and to the presence of additional injury. IL-1β modulates inflammation and multiple cell functions in basal conditions. Its basal level is low and restricted to certain areas such as the hypothalamus, hippocampus and cerebral cortex. It increases during aging, associated with the increased reactivity of glial cells. Whereas interleukin-1β (IL-1β under physiological conditions is involved in hippocampal-dependent memory and LTP, higher levels of IL-1β impair memory and neural plasticity (Avital et al., 2003; Ross et al., 2003). IL-1β induces synaptic depression and neurotransmitter release, including acetylcholine and glutamate (Murray et al., 1997).. 221. IL-1 is associated with multiple CNS injuries, either contributing to or limiting neuronal damage (Rothwell and Luheshi, 2000). In AD, IL-1 expression is induced early during plaque formation (Akiyama et al., 2000; Rothwell and Luheshi, 2000); so early, that it suggests that IL-1 participates in both amyloid plaque formation and neurodystrophic changes. Of special relevance is the observation that IL-1α may be the link between increased expression of APP and head trauma (Griffin et al., 1994) as well as with other forms of injury like epilepsy (Sheng et al., 1994). It is proposed that IL-1β induces or potentiates cytotoxicity because both IL-1β and TNF-α (through activation of NFκB, ERK and JNK signal transduction pathways) induce iNOS expression and NO production. However, IL-1 can exert beneficial effects, particularly when released in modest amounts (Mrak et al., 1995; Basu et al., 2004). It promotes remyelinization (Arnett et al., 2003) and upregulation of growth factors needed for neuronal survival (De Kosky et al., 1996; Herx et al., 2000). IL-1β increases TGFβ1 production and has a synergic effect with the neuroprotective activity of NGF (Vincent et al., 1997), further increasing neuronal viability. TNF-α is expressed in several regions of the CNS in pathological conditions, whereas its expression in healthy brain is controversial (Vitkovic et al., 2000). It has been shown that, like IL1β, TNF-α also can modulate synaptic activity and release of neurotransmitters by neurons. However, upregulation of TNF-α by pro-inflammatory stimuli or injury has been involved in cell death and inflammation. On the other hand, it also has a protective role in animal models for demyelizating diseases and traumatic brain injury (Arnett et al., 2001). Those observations lead to the proposal that TNF-α could be pro-inflammatory at early acute stages, but anti-inflammatory during the chronic phase. TGF-β1 has prominent roles in tissue development, homeostasis and repair (Akiyama et al., 2000). There are low concentrations of TGF-β1 in normal brain tissue, whereas its expression is increased in the injured brain and in several pathologic states including ischemia (Krupinski et al., 1996; Zhu et al., 2000; Meda et al., 2001). It is involved in various neurodegenerative pathologies (Flanders et al., 1998), being considered a neuroprotective factor (Dhandapani et al., 2003). TGF-.

(8) 222. R. VON BERNHARDI. β1 increases with age in the nervous system, apparently in response to glial activation (Nichols. 1999), whereas it decreases in several non neuronal tissues. AD patients show elevated levels of TGF-β1 (Rota et al., 2006). However, they also show reduced levels and altered sub cellular location of specific Smad proteins (Colangelo et al., 2002; Ueberham et al., 2006), the major transduction pathway mediating its anti-inflammatory effects (Katsel et al., 2005). We have shown that TGF-β1 secreted by hippocampal cells modulates the production of NO and super oxide radicals by microglial cells (Herrera-Molina and von Bernhardi, 2005), inhibits the induction of NOS (Vincent et al., 1997; Mc-Cartney-Francis and Wahl, 2002) and the production of IL-1 and TNF-α. Moreover, we showed that the principal source of TGF-β under proinflammatory conditions are astrocytes (Ramírez et al., 2005) regardless of whether neurons secrete more at basal conditions. Treatment with exogenous TGF-β1 has a protective effect on Aβ induced neurotoxicity (Prehn et al., 1996). The neuroprotective effect can be direct, activating the production of cell survival-promoting proteins like members of the Bcl-2 family and proteins that participate in calcium homeostasis (Mattson, 2000; Zhu et al., 2004a), or indirect, by preventing over-activation of microglial cells (De Sampaio et al., 2002, Eyüpoglu et al., 2003). On the other hand, TGF-β1 is also associated with pro-inflammatory events and the potentiation of neurotoxicity (Brown, 1999). We have shown that both anti-inflammatory cytokines like TGF-β and pro-inflammatory cytokines like IL-1β modulate the inflammatory response of microglia, decreasing NO production. Modulation of oxidative molecules involved ERK and p38 MAPKs transduction pathways. IL-1β and TGF-β inhibit IFNγ-induced ERK phosphorylation with different kinetics; fast and transient for IL-1β and prolonged for TGF-β1, which inhibits ERK activation after hours and persists for a long time (Saud et al., 2005). The inhibition of microglial activation by IL-1β suggests that the timing of the activation of the different pathways plays a key role in determining the cellular response. IL-1β, which is induced early after injury, could mediate the auto regulation of microglial cells activation. If unable to resolve the inflammatory condition, TGF-β1 pathways would be activated at later stages. I pro-. pose that impairment of the modulatory effect of TGF-β1 on neuroinflammation promotes cytotoxicity and Aβ amyloidogenesis, establishing the grounds for AD. PARTICIPATION OF GLIAL CELLS IN NEURODEGENERATIVE DISEASES Increased numbers of microglial cells are observed in most neurodegenerative diseases. Although they release a variety of molecules, such as ROS, nitrogen intermediaries, cytokines and chemokines (Meda et al., 2001), complement factors, etc., capable of inducing cell damage (Akiyama et al., 2000; Eikelenboom et al., 2002), their primary function is to protect the brain. Microglial cells constitute the resident macrophage cells and orchestrate the inflammatory response to injury. They synthesize several cytokines responsible for autocrine regulation and communication with neurons, astrocytes, and leukocyte infiltrates (Giulian and Corpuz, 1993; Hanisch, 2002). When unstimulated, microglia express more anti-inflammatory cytokines (TGF-β1 and IL-10) than the pro-inflammatory cytokines (IL-1β, IL-6, IL-12, interferon gamma (IFN-γ and TNF-α). When stimulated with a strong activator pro-inflammatory cytokines are up regulated while anti-inflammatory cytokines are down regulated (Xiao et al., 1996). However, all inflammatory activations are not equivalent. Microglia could produce high levels of radical species without becoming phagocytic, or vice versa, generating different outcomes in terms of tissue damage and Aβ removal. Ignoring the complexity of glial activation is an oversimplification that precludes adequate understanding of the brain immune response. There is controversy as to whether activation of microglia is beneficial or harmful (Giulian et al., 1993). Probably both are true since microglial activation is a gradual response. Surveillance microglia sense and are attracted to the site of injury where they proliferate and undergo functional changes, including expression of immunity mediators and release of inflammatory modulators (Meda et al., 1999; Combs et al., 2001; Nguyen et al., 2002; Smits et al., 2000; 2002). Several of the modulators released by microglial are needed for the activation of protective mechanisms and induction of neurotrophic factors. The protective role of microglia is.

(9) GLIAL CELL DYSREGULATION & ALZHEIMER DISEASE. further suggested by the ability of invading myeloid-derived microglial cells to reduce amyloid plaques in APP transgenic mice (Simard et al., 2006). It appears adequate to propose that microglia are neuroprotective against the noxious stimuli in early stages of activation (Streit, 2002), but under sustained activation, they could become cytotoxic (Eyüpoglu et al., 2003). Autopsy studies of AD patients show activation of microglia (Lue et al., 1996). It is associated with the evolution of amyloid deposits towards mature plaques (Sheng et al., 1997; Wegiel et al., 2000). Positron emission tomography reveals microglial activation in specific cortical regions in patients from early stages of AD (Cagnin et al., 2001). The role of such microglial cells is controversial (Eikelenboom and van Gool, 2004), as there is evidence that they contribute to both the phagocytosis (Matsuoka et al., 2001; D'Andrea et al., 2004), and the deposition of Aβ (Wegiel et al., 2001; Eikelenboom and van Gool, 2004). Upon activation by Aβ (Hashioka et al., 2005), microglial cells secrete inflammatory cytokines (IL-1, IL-6 and TNF-α), chemokines (IL-8, MCP-1 and MIP-1) and the growth factor M-CSF (Lue et al., 2001b). In combination with TNF-α, NO is associated with microglia-mediated neurodegeneration. Activated microglia also produce large amounts of O2._ by the "respiratory burst" (Eikelenboom et al., 2002). Thus, microglial mediated neurotoxicity depends both on radical species and cytokines (Benzing et al., 1999; Mehlhorn et al., 2000). Furthermore, there is evidence that cytotoxicity of pro-inflammatory factors such as LPS depends on the presence of microglial cells. Moreover, persistent microglial activation is observed only when cells are exposed to multiple pro-inflammatory stimuli (von Bernhardi, unpublished observations). The ability of Aβ to elicit NO release and oxidative stress is controversial (Forloni et al., 1997; Hu et al., 1998; Meda et al., 1999; Ishii et al., 2000). Some results indicate that Aβ triggers production of NO and inflammatory molecules in microglia and astrocytes in vitro (Meda et al., 1995; Malchiodi-Albedi et al., 2001; Rogers et al., 2002). In contrast, we have observed that Aβ only induces a small increase in nitrite production in microglia, which is reduced in the presence of astrocytes. However, abundant NO is produced by astrocytes. 223. and microglial cells activated by pro-inflammatory molecules (von Bernhardi et al., 2001), mediated through the activation of iNOS. Moreover, Aβ plus LPS and IFNγ-induced nitrite production are synergistic (von Bernhardi and Eugenín, 2004). On the same line, glial cell reactivity to APP is low, but it is potentiated by pro-inflammatory molecules (von Bernhardi et al., 2007). The synergy between Aβ/ APP and pro-inflammatory factors led me to postulate that glial over reactivity to Aβ/APP occurs only under certain inflammatory conditions. The implications for neurodegenerative processes are critical, since microglia and astrocytes are activated during aging and in most CNS diseases. It is possible that stimuli resulting from the multiple inflammatory mediators upregulated under those conditions could be necessary in addition to Aβ/ APP for the anomalous microglial activation. Astrocytes, on the other hand, are the structural and trophic support of the CNS (Kirchhoff et al., 2001), needed for neuronal housekeeping, synapse formation and modulation (Nedergaard, 1994). Astrocytes play an important role in inflammatory processes. Besides cytokines, they also secrete neurotrophic factors such as nerve growth factor (NGF), S100β, brain derived growth factor (BDNF) and neurotrophins (Blondel et al., 2000; Hock et al., 2000; Mrak and Griffin, 2001). In AD brains, astrocyte activation is prominent around Aβ deposits. They work cooperatively with microglia and contribute to the local inflammatory response in senile plaques, exerting mutual regulatory activity over each other (Giulian et al., 1993; Ramírez et al., 2005). Evidences are contradictory as to whether reactive astrocytes at sites of Aβ deposition have damaging or neuroprotective functions (Wyss-Coray and Mucke, 2002). Astrocytes are neuroprotective (Smits et al., 2001; Wyss-Coray et al., 2003; Sortino et al., 2004; von Bernhardi and Eugenín, 2004), but they also secrete pro-inflammatory mediators such as IL-1, MCP-1, RANTES and TNF-α (Smits et al., 2001), and show deleterious effects in AD (Abramov et al., 2003; Nagele et al., 2004). On the other hand, astrocytes inhibit microglial cytotoxicity (von Bernhardi and Ramírez, 2001; von Bernhardi and Eugenín, 2004; Ramírez et al., 2005). Astrocytes isolated from AD patients produce high levels of anti-inflammatory cytokines such as TGF-β1 and reactive astrocytes from.

(10) 224. R. VON BERNHARDI. AD-transgenic mice secrete TGF-β and IL-10 (Apelt and Schiebs, 2001). Because TGF-β1 production can be inhibited by TNF-α, it is possible that inflammatory factors, under certain circumstances down regulate astrocytes' protective antiinflammatory responses. MODULATION OF GLIAL ACTIVATION Glial cells and neurons influence each other. Microglial cells and astrocytes produce several trophic factors and extracellular matrix molecules that are needed by neurons. Cytokines secreted by microglia are also needed to activate astrocytes, for them to secrete growth factors involved in the survival and repair of neurons, whether they also secrete several inflammatory mediators. This duality of potentially protective and damaging effects suggests that astrocytes can play a neuroprotective role. However, as we will discuss here, impairment of their modulatory capability or their inability to modulate a persistent activation could lead to neurotoxicity. Conversely, neurons provide feedback modulating glial activation. Injuries or conditions affecting neuronal function can impair their modulatory effect. Active healthy neurons provide inhibitory factors regulating the synthesis of proteins associated with reactive gliosis and suppressing their inflammatory responses (Neumann and Wekerle, 1998), whereas damaged neurons can induce glial activation (Sudo et al., 1998). Hippocampal cultures secrete soluble factors, such as TGF-β, capable of modulating O2._ and NO production by glial cells (Herrera-Molina and von Bernhardi, 2005). However, neurons also produce inflammatory mediators, including eicosanoids (Pasinetti, 1998), C-reactive protein, amyloid protein, and complement factors (Yasojima et al., 2000), capable of further stimulating the glial inflammatory response. Microglial cytotoxic activity is modulated in various ways, including the induction of antioxidant enzymes and anti-inflammatory cytokines (IL-1Ra, IL-4, IL-10 and TGF-β1). Their activity also is modulated by astrocytes. Astrocytes affect the interaction of microglia with Aβ, reducing microglial activation (von Bernhardi and Ramírez, 2001), altering their phagocytic capability (DeWitt. et al., 1998) and attenuating the production of ROS and TNF-α (Smits et al., 2001). Astrocytes abolish Aβ cytotoxicity, both directly (Ramírez et al., 2005) and indirectly through microglial activation (von Bernhardi and Eugenín, 2004). Astrocytes exposed to LPS and IFN-γ prevent Aβ-induced apoptosis in hippocampal cell cultures. The protective effect is absent in cultures depleted of astrocytes and depends on the increased expression and secretion of TGF-β1 (Ramírez et al., 2005). We showed that TGF-β1 can be one of the modulating factors, since microglial modulation by mixed glialneuron cultures can be abolished by antibodies specific for active TGF-β1 (Herrera-Molina and von Bernhardi, 2005). Taken together, evidence suggests that astrocytes are pivotal in the modulation of inflammation of the CNS and have major regulatory effects on microglia and neurons exposed to Aβ. However, under strong inflammatory stimuli, astrocytes are unable to inhibit NO production by microglial cells (von Bernhardi et al., 2001; 2007; von Bernhardi and Eugenín, 2004). Not only the type of inflammatory stimuli, but also the duration of the stimuli are relevant for the outcome of the activation of astrocytes and their effect on microglial cell modulation. Whereas stimulation of astrocytes with 1 µg/ml LPS + 10 ng/ml IFNγ for up to 24 h resulted in inhibitory modulation of microglial cells (von Bernhardi and Eugenín, 2004), astrocytes exposed to the same proinflammatory condition for 48 h or longer failed to inhibit microglial cell activation, potentiating their neuroxicity (von Bernhardi, unpublished results). Those results suggest that certain inflammatory conditions could impair regulatory functions normally performed by astrocytes; effect that could be an important pathogenic mechanism for neurodegenerative diseases. RECEPTORS MEDIATING CELL INTERACTION WITH Aβ IN AD The way Aβ interacts with cells is relevant for understanding its neurotoxicity and glial cellmediated neuroinflammation. Several membrane proteins bind Aβ, including Scavenger Receptors (SR) SR-A, SR-B, (Husemann et al., 2002) and CD36 (Coraci et al., 2002), whose activation is associated with an inflammatory response to the receptor for advanced glycosilation end-products.

(11) GLIAL CELL DYSREGULATION & ALZHEIMER DISEASE. (RAGE), inducing oxidative stress and production of cytokines (Lue et al., 2001b); and to the SR macrophage receptor with collagenous structure (SR-MARCO), a member of the SR-A family (Alarcón et al., 2005). SR expression changes with age and cell type. Neonatal microglial cells in culture express SR-A, SR-BI and CD36 (Paresce et al., 1996). In contrast, adult mouse microglia express SR-B, low levels of CD36 (Husemann et al., 2002), and SR-A is undetectable (Bell et al., 1994). However, SR-A is expressed by activated microglia near senile plaques (Christie et al., 1996). Unlike microglia, astrocytes only express SR-BI (Husemann and Silverstein, 2001), mannose receptor and SR-MARCO (Alarcón et al., 2005). The binding of Aβ to SRs can be especially relevant for understanding the association of inflammation with AD (Husemann et al., 2002). Microglial cells express various receptors that bind Aβ under normal and pathological conditions. They bind to, internalize, and can degrade Aβ. Aβ binding is related to the upregulation of expression of some of the SR, the secretion of chemokines and proinflammatory cytokines like IL-1β, induction of respiratory burst with increased production of ROS, and the activation of various signaling transduction pathways. On the other hand, the most restricted expression of SRs by astrocytes, which also appear to be able to phagocytose Aβ, could result in a different activation response. These observations, and the presence of Aβ in astrocytes surrounding amyloid plaques (Wegiel et al., 2000), led me to propose that impairment of Aβ clearance and the activation of signal transduction pathways secondary to Aβ binding to astrocytes could be involved in the inflammatory response and participate in Aβ accumulation. Several pathways seem to be involved both in microglial and astrocytes activation by Aβ (Akama et al., 1998), including tyrosine kinase-dependent pathways (McDonalds et al., 1998; Combs et al., 2001) and NF-κB. Several of the pathways activated by Aβ are common with those activated by IFN-γ and LPS (Nguyen et al., 2002). The interaction of the various SRs with Aβ could be complementary and mostly associated with the induction of an inflammatory response. Binding of RAGE leads to the expression of several pro-inflammato-. 225. ry molecules mediated by the activation of NFκB transcription factor (Hofmann et al., 1999), and induces RAGE expression. Such a positive feedback can contribute to chronic inflammation and tissue injury. NFκB is also activated by pro-inflammatory cytokines such as IL-1β and TNF-α and is critical for microglia-mediated neurotoxicity induced by Aβ (Chen et al., 2005). However, competition assays with ligands for RAGE do not modify Aβ-induced response, suggesting that other receptors also mediate Aβ neurotoxicity (Liu et al., 1997). Binding of Aβ to CD36 activates microglia to secrete ROS, pro-inflammatory cytokines such as IL-1β and TNF-α and several chemokines active on microglial cells, which amplify the inflammatory response (El Khoury et al., 2003). It activates a CD36-dependent signaling cascade involving Src kinase family members, the inflammatory mediators Lyn and Fyn and the mitogen-activated protein kinase p44/42 (El Khoury et al., 2003). Ligand binding to SR-A stimulates activation of PI3-kinase and proteintyrosine kinase and MAPK pathways. Binding to SR-A also increases pro-inflammatory cytokines such as IL-1β and TNF-α (Hsu et al., 2001). RECAPITULATION Increased levels and deposition of Aβ in AD occurs secondary to inflammatory changes associated with aging. There is in vivo evidence that deposition of Aβ occurs after oxidative stress or secondary to neuronal stress and that its aggregation is increased by inflammatory conditions. Evidence suggests that Aβ has several potential deleterious effects when its level and aggregation are increased. The increased generation and neurotoxicity of Aβ in AD can be triggered by various stimuli events added to a basal inflammatory environment (e.g., as observed in aging). These events result in increased processing of APP into Aβ and altered interaction of Aβ with glial cells, impairing its clearance and potentiating a reactive inflammatory response. Acknowledgements The author's research is supported by grant FONDECYT 1040831..

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