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Neuroglia in neurodegeneration

Neuroglia in neurodegeneration Michael T. Henekaa,⁎, José J. Rodríguezb,e, Alexei Verkhratskyc,d,e,⁎ aKlinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Sigmund-Freud-Str. 25, 53127 Bonn, GermanybIKERBASQUE, Basque Foundation for Science, 48011, Bilbao, SpaincDepartment of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, SpaindFaculty of Life Sciences, The University of Manchester, Manchester, UKeInstitute of Experimental Medicine, ASCR, Prague, Czech Republic Neuroglial cells are fundamental for control of brain homeostasis and they represent the Accepted 19 November 2009 intrinsic brain defence system. All forms in neuropathology therefore inevitably involve Available online 26 November 2009 glia. The neurodegenerative diseases disrupt connectivity within brain circuits affectingneuronal–neuronal, neuronal–glial and glial–glial contacts. In addition neurodegenerative processes trigger universal and conserved glial reactions represented by astrogliosis and microglial activation. The complex of recently acquired knowledge allows us to regard the neurodegenerative diseases as primarily gliodegenerative processes, in which glial cells determine the progression and outcome of neuropathological process.
2009 Elsevier B.V. All rights reserved.
Alzheimer's diseaseParkinson's diseaseDementiaAmyotrophic lateral sclerosis Physiological functions of glial cells: Neuroglia as the brain homeostatic machinery . . . . . . . . .
2.1.1. Astrocytes organise the brain matter . . . . . . . . . . . . . . . . . .
2.1.2. Astrocytes form neuronal–glial–vascular units and provide neurones with metabolic support . .
2.1.3. Astrocytes control extracellular homeostasis of ions and neurotransmitters . . . . . . .
2.1.5. Astrocytes mould the CNS synapses and participate in synaptic transmission . . . . . . .
Microglia—the brain surveillance system. . . . . . . . . . . . . . . . . . .
Neuroglia determines the outcome of neurological pathology . . . . . . . . . . . . . . .
⁎ Corresponding authors. M.T. Heneka is to be contacted at Klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Sigmund- Freud-Str. 25, 53127 Bonn, Germany. A. Verkhratsky, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
E-mail addresses: (M.T. Heneka), (A. Verkhratsky).
0165-0173/$ – see front matter 2009 Elsevier B.V. All rights reserved.
doi: Neuroglia—the concept features, demonstrate a profound functional heterogeneity indifferent brain regions and at different developmental stages.
The complexity of the cellular circuitry of human brain is Nonetheless, each and every neuroglial cell has a conceptual unparalleled by any other living system known so far. The countenance to keep the brain homeostasis, starting from the neural cells are exceedingly densely packed within a strictly control of local molecular environment to providing the limited volume of the skull, thus requiring a specific attention intrinsic brain defence system. These glial homeostatic to the control of brain homeostasis throughout early deve- functions are many, and their failure inevitably signals brain lopment and postnatal functioning. This specific requirement pathology. This essay is specifically dedicated to the role of is manifested in the highly developed brain–blood barrier, neuroglia in neurodegenerative processes, yet prior to embark which essentially limits the impact of bodily homeostatic into the realms of disease we shall provide a brief overview of systems on the central nervous system (CNS). The brain physiological functions of main types of glial cells.
homeostasis therefore is entrusted to specific population ofneural cells known as neuroglia.
The concept of neuroglia as a connective tissue into which Physiological functions of glial cells: all elements of the central nervous system (CNS) are Neuroglia as the brain homeostatic machinery embedded was introduced by Rudolf Virchow ). In the course of late 19th–early 20th century the cellular nature and morpho-functional heterogeneity of neuroglial cells were firmly Astrocytes organise the brain matter The astrocytes provide for the micro-architecture of the grey matter by dividing it (through the process known as "tiling" recent decades the functional relevance and versatility of into relatively independent structural neuroglia that is involved in all activities of the CNS, from units. Each protoplasmic astrocyte dwelling in the grey matter structural and metabolic support to information processing, establishes its own territory within the limits of its elaborated has started to be fully appreciated ( arbour of processes; this domain organisation exists in both rodents and humans these anatomical domains astroglial membranes cover syn- the evolutionary uniqueness of human glial cells aptic contacts and establish contacts with neuronal mem- ) indicates their role in the formation of human branes as well as with blood vessels. Evolution of the CNS and appearance of the intellect coincided with a remarkable The neuroglia appeared early in evolution, when primitive increase in the size and complexity of astroglial cells nervous systems began to emerge, and became the predomi- That is the average diameter of the nant cellular type in the brain of Homo sapiens. The main types domain belonging to a human protoplasmic astrocyte is ∼2.5 of neuroglia are represented by astrocytes (named so by times larger that the domain formed by a rat astrocyte (142 vs.
Michael von Lenhossek )), oligodendrocytes 56 μm). The volume of the human protoplasmic astrocyte (christened by Pio del Rio-Hortega NG2 domain was ∼16.5 times larger than that of the corresponding positive glia (initially revealed by William Stallcup ( domain in a rat brain. Furthermore, human protoplasmic ) and identified as a separate class of astrocytes have ∼10 times more primary processes emanating glia in the recent decade ( from their somatas, and correspondingly much more complex and microglia (discovered by Rio- processes arborisation. Likewise, the fibrous astrocytes, pop- Hortega The cellular elements ulating the white matter are ∼2.2 times larger in humans comprising each of these groups, although having common when compared to rodents. The astroglial domains that parcellate the grey matter can be the unifying structures, port into the astrocytes. An increase of Na+ concentration in which, by covering many synapses (about 20.000–120.000 in the cytosol of astrocytes stimulates glycolysis, which results rodents and 270.000 to 2.000.000 in humans), can integrate and in synthesis of lactate; the latter is then transported to regulate the activity of large synaptic sets ( neurones by monocarboxylase transporters 1 and 2, thus providing active cells with much needed energy substrate The single astrocytic domains are further integrated by virtue of gap junctions ) into astroglial syncytia. The gap junctional Astrocytes control extracellular homeostasis of ions and contacts are localised on the peripheral processes where two astroglial domains overlap; the actual areas of contacts Control of the extracellular concentrations of ions, metabo- between neighbouring astrocytes are quite small. It is lites and neuroactive molecules is of a paramount importance interesting that the overlapping areas of human astrocytes for brain function. Neuronal excitability is maintained by were ∼20 times larger than in rodents relatively large transmembrane fluxes of ions, which are which possibly indicates a higher degree of coupling. Gap moved by electro-chemical gradients. These fluxes affect the junctions provide for a glial information-transfer system, as extracellular concentrations of ions, which in turn change they form pathways for intercellular diffusion of many these gradients. The accumulation of extracellular K+ is molecules, which convey the long-range signalling. One of particularly important as it accompanies the repolarisation these signalling pathways, represented by diffusion of second phase of action potentials; under physiological conditions the messenger InsP3 with subsequent Ca2+ release is well char- extracellular potassium concentration ([K+]o) can rise up to 10– acterised as propagating Ca2+ wave 12 mM (Control of extracellular K+ both Ca2+ release concentration is accomplished by astrocytes through local K+ and Ca2+ waves are considered to be a substrate for astroglial uptake involving inward rectifier K+ channels and K+ spatial The spatial K+ buffering provides for the ). However, other molecules, such as, redistribution of K+ from the areas with elevated [K+]o to the for example, metabolic substrates ) can regions with low [K+]o. This spatial buffering occurs either in form alternative inter-glial signalling systems. The astroglial glial syncytia or within the confines of single radial Muller glial syncytia are formed within larger anatomical structures: for cells, through the process known as K+ siphoning ( example, in the somatosensory cortex, astroglial networks are confined to individual barrels with very weak (if any) The astroglial transport of ions, which accompanies inter-barrel coupling ( neuronal activity (e.g. K+ uptake through KIR channels, or Na+ accumulation alongside with glutamate transportation)requires concomitant movement of water. Control of water Astrocytes form neuronal–glial–vascular units and homeostasis is also accomplished by astrocytes. High synaptic provide neurones with metabolic support activity is associated with local shrinkage of the extracellular The concept of astrocytes forming a metabolic connection space, which is regulated by water transport across astroglial between neurones and blood vessels was introduced by membranes and water redistribution through the glial syncy- Camillo Golgi after his discovery of astroglial endfeet embrac- tium. Water enters and leaves the astroglial syncytia through ing brain capillaries (). The astroglial domains are aquaporins channels (mostly of AQP4 type) which are instrumental in establishing such a connection through concentrated in perisynaptic processes and in the perivascular moulding the neuronal–glial–vascular units, which integrate and subpial endfeet Further- neural circuitry with local blood flow. Indeed, most protoplas- more, K+ buffering and water redistribution are tightly mic astrocytes contact neighbouring capillaries through the coordinated and alteration of water flux impairs upon K+ perivascular processes forming an endfoot ( buffering ().
). Astrocytes also forge a functional link between neu- Astrocytes play the central role in the extracellular rones and blood vessels. An increase in focal neural activity homeostasis of neurotransmitters and most importantly of triggers rapid vasodilatation, the phenomenon known as glutamate. Glutamate, despite being the main excitatory functional hyperaemia An increase transmitter in the CNS, is the most powerful neurotoxin, and in neuronal activity within the astroglial domain triggers Ca2+ every excess of glutamate in the extracellular spaces triggers signals, which enter astrocyte endfeet and result in the release excitotoxic neuronal death. Astrocytes are the main sink of of vasoactive substances. The latter can trigger either vasocon- glutamate in the brain; from the bulk of glutamate released striction or vasodilatation during synaptic transmission, about 20% is accumulated into postsynaptic neurones and the remaining 80% is taken up by perisynaptic astrocytes The metabolic support of neurones is achieved through a glucose-lactate shuttle operative within the astroglial Glutamate transport is accomplished by specific glutamate domains. Astrocytes accumulate about 50% of glucose enter- transporters (represented by ing the brain tissue, and store it in the form of glycogen. An several types (EAAT1 to EAAT5 in human brain). The EAAT1 increase in neuronal activity, accompanied with an increased and EAAT2 (known in rodent brain as glutamate/aspartate glutamate release, results in Na+-dependent glutamate trans- transporter, GLAST, and glutamate transporter-1, GLT-1) are expressed exclusively in astrocytes and are which are absent in hippocampus responsible for the bulk of glutamate uptake. The transloca- ). Gliotransmitter tion of glutamate is powered by transmembrane ion gradients, release actively modulates synaptic transmission by activat- and the transport of a single glutamate molecule requires an ing various neuronal receptors such as, for example, NMDA or influx of three Na+ ions and one H+ ion coupled with the efflux adenosine receptors ( As a result Na+/glutamate transporter is electrogenic and its Astrocytes do not only participate in synaptic transmission— activation produces a net inward sodium current they act as key elements in synaptogenesis, in synaptic ), which may substantially affect intracellular Na+ maturation and maintenance. In the in vitro condition, the concentration. The excessive sodium accumulation accompa- addition of astrocytes triggers very substantial increase (up nying glutamate accumulation can be counterbalanced by Na+ to seven times) in synapse formation efflux through Na+/Ca2+ exchanger working in the reverse Astrocytes produce and secrete cholesterol which is critically important for synapse formation Astrocytes are also crucial for the recovery of glutamate to and secrete variety of factors needed for both synaptic the presynaptic terminal. After entering the astroglial cells maturation and maintenance glutamate is converted into glutamine by the astrocytic- ). Furthermore astrocytes synthesise and release specific glutamine synthetase thrombospondins 1 and 2 that promote synaptogenesis both ). Glutamine, being non-toxic, can subsequently be safely in vivo and in vitro and are critically important for post-lesion transported back to the presynaptic terminal through the synaptic plasticity, remodelling and regeneration ( extracellular space; after entering the neuronal compartment glutamine is converted into glutamate, thus accomplishingthe glutamate–glutamine shuttle.
The function of oligodendrocytes is to produce the myelin The ability of astrocytes to release chemical transmitters sheaths that insulate axons in the CNS. The myelin sheath is (named gliotransmitters in order to distinguish them from composed from several specific proteins including myelin neurotransmitters) is fundamental for their involvement in proteolipid protein (PLP), myelin basic protein (MBP) and information processing in neuronal–glial networks. The myelin associated glycoprotein (MAG) gliotransmitters include glutamate, ATP, D-serine, GABA, . The myelin sheath being a fatty taurine and possibly other molecules (see insulating layer facilitates the saltatory conduction of action potentials (So far four different phenotypes (I–IV) subdivide oligodendrocytes. Developmentally, all four types for review). The gliotransmitters of oligodendrocytes are likely to originate from common can be released from astrocytes through Ca2+-dependent oligodendrocyte progenitor cells (OPCs) nestled in the SVZ.
exocytosis (), by diffusion though large pore After the migration to their target regions OPCs differentiate channels (e.g. P2X7 receptors, hemichannels or volume- and mature up-regulating the expression of myelin proteins, activated Cl− channels and begin to form the myelin sheath transporters (reversed glutamate transporter () or a cystine-glutamate antiporter Astrocytes mould the CNS synapses and participate in The NG2 glial cells (identifiable by the expression of NG2 synaptic transmission chondroitin sulphate proteoglycan (which Most of the CNS synapses are formed by three elements—the are also known as synantocytes (from the Greek synanto for astroglial perisynaptic process, the presynaptic neuronal contact ()), are present throughout the terminal and the postsynaptic neuronal membrane—the developing and adult brain ( structure generally known as a tripartite synapse ( ). Although NG2 cells express various markers, which are characteristic for oligodendrocyte progenitor cells, has a dual role in this tripartite synapse. First, by the virtue of they have some distinct features, which permit classifying neurotransmitter receptors expressed in the astroglial mem- them as a separate type of glia. The NG2 cells have a stellate brane, the astrocyte can sense the transmitter release from morphology with many primary processes, which bifurcate to the neuronal terminal, and secondly by releasing gliotrans- form a process arborisation with a diameter of about 100 μm mitters the astrocyte can modulate the efficacy of the synapse.
Astroglial cells can potentially express virtually every neuro- Physiologically many NG2 cells express voltage-gated Na+ transmitter receptor ( channels which, at least in cortical NG2 cells are dense enough to generate action ). This expression however, is strictly controlled in vivo potentials (In addition, the NG2 glia and astrocytes from different brain regions are endowed with express Ca2+ permeable AMPA receptors, GABA receptors ( very distinct complement of receptors. The cortical astrocytes, and, most likely, purinoceptors for example, express functional NMDA and P2X1/5 receptors, In the hippocampus the NG2 glia receive functional synaptic inputs from CA3 pyramidal neurones and GABAergicinterneurones (). The NG2 cells may be Neuroglia determines the outcome of important for integration in the brain because their processes neurological pathology pass through several neuronal layers and traverse grey andwhite matter. Finally, the NG2 glial cells are highly plastic Glial cells are fundamental for the control of brain homeosta- progenitor cells that can give rise to astrocytes sis, and they represent the intrinsic brain defence system.
) and may be even to neurones.
First, the homeostatic systems expressed in astrocytesprevent homeostatic imbalances triggered by various types Microglia—the brain surveillance system of stressors applied to CNS. Second, two types of glia—theastrocytes and microglia—possess evolutionary conserved Microglial cells are the resident macrophages of the CNS.
programs of activation in response to brain damage. A variety Microglia constitute around 10% of all cells in the nervous of brain insults trigger a condition generally referred to as system. These cells are of myeloid origin ( reactive gliosis, which includes astrogliosis and activation of ) and they enter CNS during the early postnatal period microglia. The astrogliosis ( through the so-called "fountains of microglia" ( is essential for both limiting the areas of ). After entering the CNS, these cells disseminate through damage (by scar formation through anisomorphic astrogliosis) the parenchyma and transform into the resting microglia. The and for the post-insult remodelling and recovery of neural resting microglial cells have small somatas and multiple fine function (by isomorphic astrogliosis). The activation of micro- processes. Every microglial cell occupies the defined territorial glia is fundamental for the brain immune response as well as domain, which does not overlap with neighbouring microglia.
for the removal of both invading infectious agents and In the physiological conditions, microglial processes are posthumous cell debris ( constantly moving scanning the microenvironment in their anatomical domains ( All these glial defence mechanisms are genuinely surviva- ). Microglia represent the innate immune system in the listic, and yet, the glial cells being homeostatic tools possess brain and thus are the first line of defence against invading (as many other biological homeostatic systems do) an pathogens and serve as specialised sensors for brain tissue inherent dichotomy—they can be protective as well as deleterious In fact, stronger brain insults may push ). Insults to the nervous system trigger a complex and glial homeostatic systems towards a damage exacerbating multi-stage activation of microglia, which results in both mode. The severe stress on astroglial energetics with a phenotypic and functional changes ( subsequent loss of ion homeostasis may trigger a massive ). This process manifested by release of glutamate (through reversed transporters or large microglia transition from a surveillance state to an activated pore channels), a substantial leak of K+ ions, release of NO and state is controlled by multiple extracellular signals acting reactive oxygen species—i.e. agents promoting neurotoxicity through a multitude of receptors. These "danger" signals are The activation and over- represented either by the disappearance of certain molecules, activation of microglia may have similar deleterious effects indicative of normal brain functioning or by the appearance of through both phagocytic activity and release of pro-inflam- new molecules associated with infectious agents, debris from matory and neurotoxic factors. All these glial reactions are damaged or dying cells or misfolded and aggregated proteins intimately involved into acute brain damage such as trauma appearing in response to a primary degenerative process or stroke. All in all "glia appears as a brain warden, and as such (the concept of "on" and "off" signalling— it is intrinsically endowed with two opposite features: it protects the nervous tissue as long as it can, but it also can act Under pathological situations, such as neurodegenerative as a natural killer, trying to eliminate and seal the damaged diseases, strokes, traumatic injuries and tumour invasions, area, to save the whole at the expense of the part ( these cells become activated, migrate to and surround damaged or dead cells, and subsequently clear cellular debris Neuroglia is also thoroughly involved in pathogenesis of from the area, similarly to the phagocytic macrophages of the many chronic neurological disorders peripheral immune system ().
Astrocytes in epileptic foci in the Activated microglia up-regulate a variety of surface receptors, temporal lobe epilepsy undergo both morphological and including major histocompatibility complex and complement functional changes (see for review). In humans, epilepsy triggers reactive astrogliosis ). They also undergo fundamental morphological changes and an increase in GFAP expression from a ramified phenotype to motile activated amoeboid cells ). The role of glutamate release from (Once they are immunostimulated in astrocytes in synchronous discharges triggering epileptiform response to neurodegenerative events, these microglia cells seizures has been proposed (although the release a variety of proinflammatory mediators including exact degree of astroglial involvement in this process remains cytokines, reactive oxygen species, complement factors, controversial (). At any rate astrocytes from a neurotoxic secretory products, free radical species and NO, human epileptic brain display spontaneous Ca2+ oscillations all of which can contribute to neuronal dysfunction and cell and have an increased gap death, ultimately creating a vicious cycle ( junctional coupling which indicates remodel- ling of signalling cascades. In addition, astroglial glutamate

Fig. 1 – Dual role of astroglial homeostatic cascades. The homeostatic cascades expressed in astrocytes control extracellular ionhomeostasis through K+ buffering, regulate movements and distribution of water, control extracellular concentration ofneurotransmitters and provide main reactive-oxygen species scavenging system. In pathological conditions, when astrocytesexperience metabolic stress, the same systems may contribute to brain damage. Failure in water transport triggers brainoedema, reversal of neurotransmitter transporters together with Ca2+-dependent exocytosis and opening of high-permeabilityplasmalemmal channels contributes to glutamate excitotoxicity; inadequate K+ buffering promotes further overexcitation ofneural cells, and glial cells begin to release ROS and pro-inflammatory factors, further exacerbating brain damage.
transport can also be important for controlling seizures their degeneration and profound damage of the white matter development, as was directly demonstrated in genetically that may result in severe dementia. A particular type of post- modified mice, which lack astroglial transporter GLT-1. These stroke dementia is represented by Binswanger's disease (or animals develop spontaneous and lethal seizures which killed subcortical dementia), which is a form of vascular dementia half of homozygous mice before they reach 6 weeks of age characterised by diffuse white matter lesions; it leads to progressive loss of memory, cognition and behavioural adapta- Astroglial cells are also involved in a variety of psychiatric tion (). The infarct occurring in disorders. The loss of astrocytes was observed in patients white matter triggers progressive death of oligodendrocytes, suffering from depression The activation of astrocytes and microglia and degeneration of axons astrocytes may also play a role in the pathogenesis of ). The primary pathological steps most likely schizophrenia, through their control over glutamate homeo- are associated with ischaemic death of oligodendrocytes.
stasis and gliotransmission. The recently developed glutamate Another ischaemia-related disease arising from death of theory of schizophrenia ) stresses the role oligodendrocytes is periventricular leucomalacia; a condition of the hypofunction of NMDA receptors, which are under that causes diffused cerebral white matter injury positive control of the gliotransmitter D-serine. The latter was This occurs mostly in prematurely born infants. The used in clinical trials with certain beneficial effects roots of this pathology can be found in (1) poor vascularisation ), once more indicating that deficient gliotransmission of white matter in premature infants and (2) the prevalence of may be involved in schizophrenia pathogenesis.
oligodendrocyte progenitors, which are particularly sensitive Pathological changes in oligodendroglia are central to the to ischaemia, reactive oxygen species and glutamate excito- broad class of diseases of white matter. Oligodendrocytes and toxicity. Thus, periods of even comparatively mild ischaemia oligodendrocyte precursors are highly vulnerable to excitotoxic result in profound damage to white matter and the demise of insults. This excitotoxic death is mediated by Ca2+ influx many oligodendrocyte progenitors. This, in turn, leads to following overactivation of ionotropic glutamate receptors and defective myelination, which further alters cerebral cortex possibly P2X7 purinoceptors development and leads to the impairment of pyramidal tracts, The oligodendroglial death can directly affect axons, causing with subsequent neurological disorders, including cerebral palsy and cognitive deficits. Last but not least, the oligoden- hypothesis of direct toxicity of the mutant gene on neurones droglia plays a central role in various demyelinating disorders, mediated through reduced free-radical buffering was not including multiple sclerosis. The pathogenesis and molecular confirmed while recent studies mechanism of these diseases was a subject of many reviews have demonstrated the key role of glial impairments in the ALS pathogenesis.
The ALS is associated with astrogliosis and microglial ) to which we address the curious reader.
activation, which was described in both humans and transgenic Finally, the microglia controls the immune response and phagocytotic after-damage clearance system of the brain.
The astrogliosis, however, is preceded by astroglial degenera- Through multiple stages of activation, microglia grades the tion and atrophy, which occurs before neuronal death and the reaction to brain lesion, being one of the most important appearance of clinical symptoms in the hSOD1G93A transgenic determinants of the course of CNS pathology mouse At later stages of the disease the reactive astroglia appears, although atrophic astrocytes are also Our knowledge about the pathological potential of neuro- present close to lesion sites. The astroglial degeneration was a glia is still rudimentary, as major attention has always been property of SOD1 bearing astrocytes, which demonstrated an diverted to the pathology of neurones. Nonetheless, it becomes increased vulnerability to glutamate, mediated through increasingly obvious that it is the glia which determine the mGluR5 receptors ). The hSOD1 bearing initiation, course and outcome of majority (if not all) diseases astrocytes also release neurotoxic factors and assist microglial of the nervous system. Indeed, loss of glial support inevitably signals neuronal demise, and glial performance decides upon ). Finally, selective silencing of the SOD1 mutant the balance of neuroprotection, neuroregeneration and neural gene in astrocytes significantly slowed the progression of ALS death, thus controlling the pathology of the brain. Specifically, in transgenic mice (). Notably, a recent glial reactions are instrumental in shaping various neurode- PET study by targeting MAO-B, which in generative processes, which we shall discuss in subsequent the CNS is almost confined to astrocytes, using C11 (L)-deprenyl, chapters that are specifically dedicated to the role of astroglia described a profound astrocytic proliferation in ALS patients.
and microglia in neurodegenerative processes.
Therefore, astrocytes can be considered as central players in APS pathology. At the initial stages, glutamate inducesgliotoxicity. The atrophic astrocytes in turn reduce synaptic Astrocytes in neurodegeneration and AD coverage and fail to perform their homeostatic and neurone-supportive functions. This initiates neurodegeneration, which The causes of neurodegenerative diseases are many, from triggers reactive gliosis; reactive astrocytes release neurotoxic traumatic or infectious attacks to intrinsic processes associ- factors and stimulate microglial activation thus supporting ated with genetic predispositions or the accumulation of the vicious circle of neurodegeneration.
sporadic errors of yet unknown origins. The neurodegenera-tive disorders, which affect the main human asset, the Wernicke encephalopathy intellect, are in essence the failures of connectivity withinbrain circuitry. The astrocytes, being involved in synaptic The combination of ataxia, ophthalmoplegia, and mental birth, maturation and maintenance, as well as in controlling changes, reflecting encephalopathy with deep thalamo-corti- the brain homeostasis and neurotransmitters balance, are cal lesions was initially described by Carl Wernicke strategically important for preserving connection in brain This encephalopathy is generally caused by a networks, and their malfunction can be critical for the deficiency of thiamine. Although the nature of neuronal death development of neurodegeneration. Indeed, recently the remains unclear, the possible failure of glutamate homeosta- pathological potential of astroglia in neurodegenerative dis- sis can assume the leading role. Indeed, specific analysis eases started to be experimentally revealed.
revealed a substantial reduction (60–70%) of the expression ofastroglial transporters EAAT1 and EAAT2 in cortical samples Amyotrophic lateral sclerosis from human tissues obtained from confirmed cases ofWernicke encephalopathy. A similar profound decrease in Amyotrophic lateral sclerosis (ALS, known in the United States astroglial glutamate transporters was found in the rat as "Lou Gehrig's disease"; named so after a baseball player thiamine deficiency model of the disease ().
who suffered and died from this pathology) was described by The failure of astroglial glutamate uptake can be the reason for Jean-Martin Charcot in 1869 ( neuronal excitotoxicity and subsequent lesions. In addition, a ). The ALS is manifested by degeneration of significant decrease in expression of GFAP, astrocytic gluta- motor neurones located in the cortex, in the brain stem and mine synthetase and astrocytic GAT-3 GABA transporter, all in the spinal cord. Clinically the ALS appears in the form of indicative of astroglial dystrophy or death, was observed in the progressive paralysis and muscle atrophy. The ALS appears in thalamus of thiamine deficient rats ().
both familial (∼10% cases) and sporadic forms. About 20% ofALS cases are associated with dominant mutations in the gene Parkinson's disease coding for Cu–Zn superoxide dismutase (SOD1) ); this mutated gene become instrumental in generating The disturbed locomotive and motor functions (which include animal models of ALS (The initial akinesia, rigidity, tremor at rest, and postural abnormalities) are prevailing clinical symptoms of the Parkinson's disease (PD— astrocytes is observed ); the degree of glial )). These symptoms arise from atrophy displayed direct correlation with the severity of the specific extermination of dopaminergic neurones in sub- dementia. In another study however, prominent astrogliosis stantia nigra with a subsequent severe impairment of nigros- and profound increase in astrocyte density (up to four to five triatal dopaminergic transmission. The systematic investigation times) was found in post-mortem tissues of the astroglial involvement into the pathogenesis of PD has not yet been performed, although existing data allow suspecting the Early and prominent astrogliosis also accompanies tha- pathological potential for astrocytes. At the late stages of the lamic dementia. In this form of pathology a specific prolifer- disease, profound astrogliotic changes were identified in sub- ation of perivascular and perineuronal astroglial processes stantia nigra, reflecting the inflammatory state accompanying changes are observed. These changes in astroglia are consid- neurodegeneration ered to be the primary pathological change, which can ). The early changes in astroglia are unknown produce dementia even in the absence of severe neuronal and yet they may play an important role in the progression of PD.
The substantia nigra has less astrocytes compared to other Astrocytes (and microglia) also play a primary neurotoxic brain region; therefore it is tempting to speculate that when role in immunodeficiency virus-1 (HIV-1) associated dementia, stressed these astrocytes fail and cease to support the dopami- or HAD In HAD significant astrogliosis and an nergic neurones, which in turn contributes to the degeneration increase in GFAP expression is observed in the entorhinal cortex of the latter. The support and protection of dopaminergic and the hippocampus The progression of neurones by astroglia is well documented in vitro HAD, however, leads to a significant astroglial cell loss through ). The addition of apoptosis, which is specifically prominent in the subjects with astrocytes to midbrain cultures increases the percentage of rapidly progressing cognitive deficits In tyrosine hydroxylase-positive (i.e. dopaminergic neurones) this type of pathology, the virus infects exclusively microglia, from 2–5% to ∼40%; the effect, which is mimicked by glial- although the dementia progresses due to NMDA-receptor conditioned medium collected from cultures of mesencephalic mediated neuronal death through necrosis or apoptosis ( astrocytes The same medium also protects ). The glutamate excitotoxicty can result from TNF-α dopaminergic neurones against cell death triggered by 1- release from infected and activated microglia. This triggers a methyl-4-phenylpyridinium (MPP+; the latter is a selectively massive release of glutamate from astrocytes following a TNF- toxic for dopaminergic neurones and is the active agent in 1- α-mediated activation of chemokine receptors of the CXCR4 methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP induced aki- type expressed in astroglial membranes ).
netic rigid syndrome, considered to be the relevant animal Incidentally, the same CXCR4 receptors can also be activated by model of PD) or by NO (promotes neurite the isoform of HIV-1 coat protein gp120IIIB, implicated in HAD growth and affects signalling cascades in these neurones ( pathology. The neurotoxicity can also be exacerbated by the release of additional inflammatory and death factors from both Furthermore, astrocytes play a central role for L-DOPA- astrocytes and activated microglia dependent PD therapy. The L-DOPA (the main agent used in clinical treatment of PD) is toxic for dopaminergic neurones in Various types of non-AD dementia (e.g. progressive supra- nuclear palsy, corticobasal degeneration and Pick's disease) ), albeit it is beneficial for these neurones in vivo.
are associated with the appearance of tau protein inclusions in The difference is all in astroglia, and indeed addition of glial- astroglial cells, which normally express very little (if at all) of conditioned medium to cultures of dopaminergic neurones tau protein ). A targeted expression of FTDP-17 prevented L-DOPA neurotoxicity and turned it into trophic tau protein (the FTDP-17 gene is associated with parkinsonism and frontotemporal dementia linked to chromosome 17) into Finally, astrocytes may promote differentia- astrocytes in a transgenic mouse model triggered age-depen- tion of stem cells into dopaminergic neurones and facilitate dent neurodegeneration, thus directly indicating that astroglia their incorporation into the neuronal circuitry can indeed be a primary cause of a chronic neurodegenerative Therefore, the early astroglial atrophy and failure to support dopaminergic neurones may be an important patho- Alzheimer's disease logical step in the development of PD.
The glial involvement in the pathogenesis of Alzheimer's disease (AD) was initially suggested by Alois Alzheimerhimself (He had demonstrated that the Astrocytes are affected in many types of dementia. Depending neuritic plaques (the extracellular deposits of fibrillar β- on the type and progression of the disease, both astroglial amyloid, which together with the tau neurofibrillary tangles atrophy and astrogliosis are observed; these two processes can represent the major histopathological markers of AD) include develop in parallel depending on the pathological stage. In the glial cells (). The AD brains are characterised by frontotemporal dementia (the clinical term covering several prominent astrogliosis, mostly observed in the cells surround- types of sporadic non-Alzheimer cognitive disruptions, which ing amyloid plaques with processes of activated astrocytes include e.g. Pick's disease and frontotemporal lobar degener- participating in formation of neuritic plaques ation) early and dramatic apoptotic death and dystrophy of

Fig. 2 – Activation of glial cells at sites of β-amyloid deposition in human brain and in APP transgenic mice. (A) Neuritic plaquesas seen and drawn by Alois Alzheimer (The plaque is surrounded by activated astrocytes; and activatedmicroglia is present at the peripheral region. Abbreviations: P1—the central part of the plaque (amyloid deposition);P2—periphery of the plaque; gaz—neurone; glz—glial cell. (B) Double immunostaining of a human brain section derived from a70 years old Alzheimer disease (AD) patient reveals GFAP positive astrocytes (blue) surrounding 6E10 positive β-amyloiddeposits (brown). (C) Double-staining for β-amyloid (brown) and CD68-positive microglia cells. Scale bar = 50 μm. (D) Doubleimmunostaining of GFAP and CD11b in a cortical section of a 12 month old APP23 transgenic mouse shows a focal and closeassociation of both markers for astro- and microglial reactivity.
The β-amyloid peptide presents activating signals for The Aβ-induced [Ca2+]i oscillations lasted for many hours and astrocytes; the exposure of cultured glial cells to aggregated were linked to neuronal death, which occurred 24 h after the β-amyloid or to amyloid plaques isolated from human AD administration of Aβ to the cultures. The inhibition of [Ca2+]i brains trigger reactive astrogliosis The Aβ oscillations prevented neuronal death ().
also induces functional changes in astrocytes in vitro: the β- In the same mixed culture model Aβ was also shown to induce amyloid peptide (Aβ1–42) and its toxic fragment (Aβ25–35) mitochondrial depolarisation and oxidative stress in astro- induced spontaneous [Ca2+]i elevations and [Ca2+]i oscillations cytes; the release of reactive oxygen species from stressed in astrocytes growing in mixed astroglial–neuronal cultures.
astrocytes caused neuronal death ().
The abnormalities in astroglial Ca2+ signalling were ob- Nevertheless, the astrogliosis is not the only astroglial served in the brains of transgenic AD mice. In these experi- reaction in the AD brains. In our recent studies, performed on ments, employing in vivo multiphoton confocal microscopy, different regions of the brains of triple-transgenic (3x-Tg-AD— the general elevation of resting [Ca2+]i was observed through- mice, both astrogliosis and astroglial out the astroglial syncytia. In addition, astrocytes located in atrophy were found (; Rodriguez and the vicinity of plaques triggered spontaneous long-distance Verkhratsky, papers in preparation; The decrease in propagating Ca2+ waves, which were absent in control animals complexity of astrocytes, which indicated their atrophy, began to be observed before the formation and consolidation of The participation of astrocytes in plaque formation initi- neuritic plaques. In a plaque infested brain the reactive ated the hypothesis of the Aβ-clearing role of astroglia ( astrocytes were concentrated around the Aβ plaques, whereas ); with subsequent astroglial degeneration astroglial cells distant to the plaques had an atrophic features.
triggered by the accumulated β-amyloid peptide. Indeed, theplating of isolated healthy astrocytes on the slices preparedfrom transgenic (APP) AD mice resulted in astrocytes migra- Microglia in neurodegeneration and AD tion towards the plaques with subsequent accumulation anddegradation of Aβ. To support this finding, some evidence Amyotrophic lateral sclerosis suggests that astroglial cells are able to phagocyte Aβpeptides, a process which may depend on their apolipoprotein The primary pathological feature of ALS is the loss of motor E (ApoE) status, suggesting that ApoE polymorphisms may neurones (which is accompanied by a robust influence the risk to develop AD by affecting astroglial Aβ glial response including the activation of microglia and phagocytosis ). In contrast, astrocytes as well as the expression of cyclooxygenase 2 endogenous astrocytes surrounding the Aβ plaques were (COX-2) and nitric oxide synthase (iNOS) in the spinal cord unable to accumulate and remove Aβ ( ). In the triple transgenic mouse model of AD (3xTg-AD; ). The histological studies of post-mortem harbouring the mutant genes for amyloid precursor protein brains and spinal cord tissue were recently supported by a (APPSwe), presenilin 1PS1M146V and tauP301L ()) study using the PET ligand PK1195, which labels the peripheral very little (if any) Aβ accumulation by reactive astrocytes was benzodiazepine receptor being expressed by activated micro- observed (These data clearly indicate glia in the brain. In this study, found the phenotypic difference between normal astroglia and evidence for increased microglial activation in the prefrontal astrocytes affected by the AD pathology. Another kind of cortex, the motor cortex, the thalamus and the pons of ALS phenotypic difference was observed in astrocytes from an AD patients. Both pathologies—the loss of motor neurones and model expressing double mutated K670N-M671L APP; these neuroinflammation, can be found in transgenic mice over- astrocytes began to express β-secretase, thus becoming expressing mutant variants of the human gene encoding for possible producers of Aβ ( copper/zinc superoxide dismutase (SOD1), which have been ). While it remains linked to inherited ALS unclear to which degree astrocyte activation contributes to Aβ generation or its clearance, it seems apparent that astrocytes appearance of activated microglia and astrocytes already at an contribute to the inflammatory component of AD. For early, presymptomatic stage of the disease in SOD1 transgenic example, astrocytes have been shown to express iNOS and mice suggests that an inflammation may contribute to motor the L-arginine-supplying enzyme argininosuccinate synthe- neurones degeneration and the suppression of the inflamma- tase and consequently contribute to NO- and peroxynitrite tory component could be neuroprotective. Indeed, increasing mediated neurotoxicity ( experimental evidence suggests an active and contributory Although astrocytes serve as a constant and role of microglia in ALS. Thus, the overexpression of mutant important source of neurotrophic factors under physiological human SOD1 in motor neurones alone did not result in conditions, in vitro and in vivo experiments suggest that significant neuronal degeneration in transgenic mice ( chronically activated inflammatory astrocytes may not gen- . A similar approach erate significant amounts of these molecules ( expressing mutant SOD1 under control of the astrocytic promoter GFAP, thus causing the astroglial expression of The AD may also impair other astroglial homeostatic protein, also failed to induce motor neurones death ( functions. For example, Aβ affects astroglial ability to accu- In contrast, the selective deletion of mutant SOD1 in mulate glutamate: treatment of rat cultured astrocytes with microglia increased the survival rate in the SOD1 transgenic Aβ1–40 reduced both expression and capacity of GLAST- and mouse model, indicating that the presence of mutant SOD1 in GLT-1 mediated glutamate uptake (). Reactive microglial cells is fundamental for their detrimental effect on and pathologically changed astrocytes are also responsible for motor neurone integrity (. The latter failures in the functional activity of neuronal–glial–vascular hypothesis was further corroborated by bone marrow trans- units. Indeed, the vascular dysfunctions, perivascular amiloi- plantation experiments in mice deficient for myeloid cells but dosis and compromised blood–brain barrier are inseparable harbouring the human SOD1 mutant. In these mice, the parts of AD pathology How astroglial transplantation of wild type bone marrow cells but not SOD1 cells are participating in these changes remains, however, an mutant bone marrow cells significantly delayed the progres- open question.
sion of the disease (

Fig. 3 – Astroglial atrophy and astrogliosis accompany the development of AD pathology in the brains of triple transgenicmouse. (A, B) Representative confocal micrographs illustrating normal control astrocytes (A) compared to the astrocytic atrophyobserved in the dentate gyrus of 3xTg-AD mice (B). The atrophy is manifested by a reduction of the size of somatas as well as inthe reduction of number of primary processes and their branching. (C) Confocal micrograph showing perivascular astrocytes innormal animals. (D) Confocal dual labelling images (GFAP in green and Aβ in red) in 3xTg-AD mice showing the close appositionof astrocytes with the Aβ accumulations. Astrocytes surround Aβ plaques and undergo astrogliosis.
Although the exact molecular mechanism by which micro- neurones by pioglitazone. This finding was further substanti- glial cells become activated in ALS remains to be determined, ated by the superior motor performance in the RotaRod35 and various approaches targeting the inflammatory component of grip latency tests of mice treated with pioglitazone. The the disease demonstrated beneficial effects. Thus, the treat- numbers of activated microglia were markedly reduced at ment of mutant SOD1 transgenic mice with minocycline sites of neurodegeneration in pioglitazone-treated SOD1-G93A improved motor performance and survival ( mice compared with non-treated mice, as were levels of COX2 ). Likewise, the inhibition of COX2 by celecoxib and iNOS proteins. also provided evidence in a or nimesulide delayed the onset of the disease mouse model of ALS that nitric-oxide-dependent peroxynitrite Using a further anti-inflamma- generation was reduced by pioglitazone.
tory treatment strategy, two studies with SOD1-G93A trans-genic mice, an established model of ALS, independently found Parkinson's disease that oral treatment with the PPARγ agonist pioglitazoneextended the survival of these mice PD is characterised by a progressive degeneration of dopami- ). Pioglitazone treatment delayed the onset of nergic midbrain neurones in the substantia nigra (SN) and disease and prevented a decrease in body weight in these becomes clinically apparent when more than 50% of SN mice in comparison with untreated SOD1-G93A mice. The neurones have been lost. Despite the decades of intensive quantification of spinal cord motor neurones revealed neuro- research, the cause of the neurodegeneration in PD is still protection in mice treated with pioglitazone, whereas non- poorly understood. Microglial activation has been found in the treated SOD1-G93A mice had lost 30–40% of these neurones at substantia nigra (SN) at sites of dopaminergic cell loss in post- comparable time points. This neuroprotective effect was mortem human brains derived from PD patients. Likewise, paralleled by the preservation of the median fibre diameter activated microglial cells are found in all animal models of PD, of the quadriceps muscle in treated mice, indicating not only a together suggesting that neuroinflammatory mechanisms are functional but also a morphological protection of motor involved in the disease process. Structurally modified α- synucleins (α-SYN), particularly nitrated species, which are are associated with neuritic plaques () released as a consequence of dopaminergic neurodegenera- and they secrete a wide variety of pro-inflammatory molecules tion, have been found to act as potent microglial immuno- Furthermore the microglia is implicated in active phagocytosis of Aβ, thus counterbalancing Additional experimental evidence leads to the the Aβ load ). The hypothesis that neuroinflammation plays an active and activation of microglia occurs in response to the formation of promoting role in the disease process based on the finding neuritic plaques. Several amyloid peptides and APP itself can act that suppression of inflammatory signalling cascades sub- as potent glial activators stantially improved the phenotypic outcome as well as ), whereas the disruption of the protected from dopaminergic cell loss and subsequent neuro- APP gene and its proteolytic products delay and decrease chemical changes in SN projection areas. Thus, iNOS inhibi- microglial activation ). Microglial cells tion by either genetic deficiency or pharmacological treatment have been suggested to be preferentially associated with certain has been found to exert neuroprotection amyloid plaque types indicating that plaque development and ). Similarly, more general anti-inflam- the degree of microglial reaction are interrelated matory approaches including the activation of the peroxisome ). However, it remains unclear whether Aβ plaque deposi- proliferator activated receptor gamma pioglitazone tion is an absolute requirement for microglial activation, or ) or treatment with the semi- whether this can already be evoked by soluble and toxic Aβ synthetic tetracycline minocyline significantly protected from species. This hypothesis is supported by a recent study where dopaminergic neurodegeneration. All of these experimental the focal activation of microglial cells becomes apparent at approaches aim to block or at least interact with mechanisms 3 months of age in APP V717I transgenic mice, which usually that finally execute neuronal cell death such as oxidative start to deposit Aβ in plaque like structures much later—at stress and cytokine-receptor-mediated apoptosis.
around 10–12 months (). In contrast, studies Microglia may, however, have also protective functions in using in vivo multiphoton microscopy using 5–6 month old B6C3- this disease, for example by secretion of anti-inflammatory and YFP transgenic mice (bearing APPswe and PS1d9x-YFP genes) neuroprotective cytokines such as TGF-β (). An suggested that microglial are recruited to Aβ plaques only after important question is, as to what extent the local inflammatory they have been formed ).
process within the substantia nigra can be influenced by The mechanisms of microglial activation by Aβ depositions peripheral inflammatory events. In a recent study Godoy et al.
are not yet clear, although several receptor systems are directly tested whether a sub-toxic dose of bacterial lipopolysaccharide implicated in this process. In particular, the activation of (LPS) is actively modulating microglia from an anti- to a pro- microglia requires P2X7 purinoceptors and Ca2+ signalling. The inflammatory state and thereby exacerbate disease progression.
exposure of cultured microglial cells to Aβ25–35 triggers Ca2+ In this experiment, LPS injection in the degenerating SN influx, the IL-1β release and P2X7-dependent membrane exacerbated neurodegeneration, worsened the behavioural permeabilisation, all being absent in cells prepared from P2X7 phenotype and caused an increase in microglial IL-1 secretion.
KO mice (). Furthermore, the intra-hippocam- Of note, IL-1 inhibition reversed these effects. Importantly, pal injection of Aβ1–42 failed to induce microglial activation (as chronic systemic IL-1 also exacerbated neurodegeneration and judged by IL-1β accumulation) in animals deficient in P2X7 microglial activation in the SN (Interestingly, in a very recent paper, Smeyne et al. showed that abdominal The activation of microglial cells by aggregated Aβ involves infection with the H5N1 influenza virus resulted in a very rapid Toll-like receptors (of TLR4 type; the TLR4 viral migration into the CNS and viral presence predominantly receptors are up-regulated in both AD brain preparations and within brainstem and midbrain nuclei (). Viral in APP transgenic mice. A spontaneous loss-of-function neurotrophism caused a robust inflammatory reaction within mutation in the TLR4 gene significantly reduced Aβ-induced these nuclei including the locus coeruleus and SN. Importantly, microglial activation Exposure of micro- the H5N1 virus induced neuroinflammation, which persisted glial cultures to Aβ also stimulated TLR2 receptors, while beyond the presence of the virus itself and caused α-SYN inhibiting TLR9 receptors ). The stimulation of aggregation and progressive neurodegeneration. Together, the TLR-associated signalling system may have dual effect in these data suggest that the brainstem nuclei such as the SN AD progression. On one hand, the activation of TLRs increases are vulnerable to peripheral infection and immunological microglial phagocytosis of Aβ (this involves p38 MAPK processes. In keeping with this, anti-inflammatory therapeutic signalling and expression of G-protein-coupled formyl peptide strategies that target proinflammatory microglial activation receptor-like 2, mFPR2; the latter likely being the sensor for Aβ may represent a future therapeutic avenue.
Atthe same time, however, the over-stimulation of TLRs may Alzheimer's disease trigger excessive release of cytokines, proteases and othercytotoxins thus promoting neural cell death ().
Next to the classical neuropathological features of AD, namely The Aβ stimulates a nuclear factor kappa B (NFκB)-depen- Aβ deposition and neurofibrillary tangle formation, neuroin- dent pathway that is required for cytokine gene transcription flammatory changes have been identified as the third important within activated microglia and reactive component of the disease. The inflammatory reactions of astrocytes. Not only Aβ, but also the carboxy-terminal 100 microglia and astroglia are intimately associated with the amino acids of APP (CT100) (which are present in senile plaques) pathogenesis and progress of AD. The activated microglial cells can induce astrogliosis and neuronal death. Exposure to CT100 results in activation of the mitogen-activated protein kinase Thus, demonstrated that (MAPK) pathways as well as NFκB ). Addition- complement activation can protect against Aβ-induced toxic- ally, other proteins involved in APP processing have been ity and may reduce the accumulation or promote the implicated in the inflammatory response. Loss of presenilin clearance of senile plaques. The AD mice expressing a soluble function in presenilin conditional knockout mice leads to form of the complement inhibitor Crry, which blocks C3 differential up-regulation of inflammatory markers in the activation, under the control of the glial fibrillary acidic cerebral cortex, such as strong microglial activation, comple- protein promoter displayed higher Aβ deposition and more ment component C1q, and cathepsin S ( prominent neurodegeneration than age-matched control Once stimulated, microglia participate in the generation and mice. However, more recently it was reported that transgenic release of a wide range of inflammatory mediators including mouse models of AD lacking C1q showed reduced pathology, complement factors, chemokines and cytokines. The comple- consisting of decreased numbers of activated microglia and ment system represents a complex and tightly regulated attack improved neuronal integrity, without changes in plaque area.
cascade designed to destroy invaders and assist in the These data suggest that at stages when fibrillar plaque phagocytosis of waste, one of the key microglial tasks under pathology is present, C1q exerts a detrimental effect on physiological and pathophysiological conditions. The compo- neuronal integrity, most likely through the activation of the nents of this system carry out four major functions: recogni- classical complement cascade.
tion, opsonisation, inflammatory stimulation and direct killing In AD, unlike in the aforementioned neurological disorders through the membrane attack complex (MAC) characterised by leukocyte infiltration, abnormal or excessive In addition to triggering the generation of a migration of inflammatory cells into the CNS has not been membranolytic complex, complement proteins interact with definitively shown to occur. Nonetheless, there is growing cell surface receptors to promote a local inflammatory response evidence that chemokines and chemokine receptors are up- that contributes to the protection and healing of the host.
regulated in resident CNS cells in an AD brain Microglial complement activation causes inflammation and ), and chemokines may contribute to plaque- cell damage, yet it is essential for eliminating cell debris and associated inflammation and neurodegeneration. Up-regula- potentially toxic protein aggregates. The complement system tion of CXCR2 expression has been observed on some consists of some 30 fluid-phase and cell-membrane associated dystrophic neurites in senile plaques ( proteins that can be activated by three different routes. The ). In addition, the expression of CCR3 and classical pathway (involving C1q, C1r, C1s, C4, C2, and C3 CCR5 is increased on some reactive microglia in AD, and MIP- components) is activated primarily by the interaction of C1q 1α is found in a subpopulation of reactive astrocytes ( with immune complexes (antibody–antigen), but activation MCP-1 has also been localised to mature senile plaques can also be achieved after the interaction of C1q with non- and reactive microglia, but is not found in immature senile immune molecules such as DNA, RNA, C-reactive protein, plaques. Furthermore, in vitro studies have demonstrated the serum amyloid P, bacterial lipopolysaccharides, some fungal ability of Aβ to stimulate the production of IL-8, MCP-1, MIP-1α and virus membranes, and most importantly, by fibrillar Aβ.
and MIP-1β from human monocytes (). For The initiation of the alternative pathway (involving C3, factor example, microglia cultured from rapid autopsies of AD and B, factor D, and properdin) does not require the presence of non-demented patients exhibit significant, dose-dependent immune complexes and leads to the deposition of C3 frag- increases in IL-8, MCP-1 and MIP-1α after an exposure to Aβ ments on target cells. Mannose-binding lectin (MBL), a lectin Although more studies are certainly needed, homologous to C1q, can recognise carbohydrates such as it is likely that plaque-associated chemokine production plays mannose and N-acetylglucosamine on pathogens and initiate a role in the recruitment and accumulation of microglia to the the complement pathway independently of both the classical neuritic plaques. Future studies using targeted disruption of and the alternative activation pathways. Like the C1 complex chemokines and chemokine receptors in mouse models of AD in the classical pathway, MBL is associated with two serine should help to clarify the role of chemokines in plaque- proteases that cleave C4 and C2 components, leading to the associated inflammation and neurodegeneration.
formation of the classical C3 convertase ( Microglia derived cytokines associated with AD include Microglial cells can produce complement proteins to several interleukins (ILs), TNF-α and TGFβ amongst others. In recognise and kill pathogens locally. Studies using RT-PCR general, cytokine production is increased in inflammatory have shown locally up-regulated complement mRNA in AD states and they function by regulating the intensity and brain, especially in the areas of primary pathology: the duration of the immune response entorhinal cortex, the hippocampus, and the midtemporal ). Thus, IL-1 induces IL-6 produc- gyrus Numerous groups have reported tion, stimulates iNOS activity ), and the association of complement proteins of the classical induces the production of M-CSF pathway, particularly the MAC, with amyloid plaques and In addition, IL-1 enhances neuronal neurofibrillary tangles in AD brains ( acetylcholinesterase activity, microglial activation and addi- Information about the functional role comes from studies of tional glial IL-1 production, with consequent activation, and mutant mice lacking complement proteins, which suggest expression of the cytokine S100β by astrocytes, thereby that impaired phagocytosis can result in immunomediated establishing a self-propagating cycle ( tissue damage and inflammation ). The IL-6 promotes astrogliosis ). However, the complement system may be Janus-faced activates microglia and stimulates and also provide beneficial action to the brain during AD.
the production of acute phase proteins (). The knockout mice deficient in IL-6 exhibit a facilitation of radial enzymes regulate the generation of a whole spectrum of maze learning over 30 days and show a faster acquisition, prostanoids, some of which may be neuroprotective and others suggesting a possible negative regulation of memory formation neurodestructive. Thus, the composition and proportion of all and consolidation processes by IL-6 (). TNF-α prostanoids together may actually determine whether the has both pro-apoptotic and anti-apoptotic effects. This proin- activity of COX enzymes is beneficial or detrimental.
flammatory cytokine accounts for most of the neurotoxic In vitro, LPS activated microglial cells and IL-1β-stimulated activity secreted by monocytes and microglia astroglial cells are capable of synthesising COX-2 ). On the other hand, TNF-α has been reported to have ). In contrast to neuroprotective properties ) in the AD brain.
peripheral monocytes, cultured rat microglia cells do not In addition to the general role of cytokines, AD-specific synthesise COX-2 in response to IL-1 or IL-6 ), interactions of certain cytokines with the APP processing suggesting that COX-2 regulation differs between CNS and pathway and Aβ may be pathophysiologically relevant. For peripheral cells. In rat microglial cell cultures, the major example, IL-1 can regulate APP processing and Aβ production in enzymatic product of COX-2 appears to be prostaglandin E2 vitro ). In turn, fibrillar Aβ has been reported to (PGE2). Because PGE2 itself is able to induce COX-2 in microglia increase neurotoxic secretory products, proinflammatory cyto- ), some sort of autocrine or paracrine kines and reactive oxygen species ( amplification of the COX-2 induction in microglial cells or a spreading of the COX-2 expression between neurones and Cultured rat cortical glia exhibit elevated IL-6 mRNA after microglial cells is possible. The PGE2 acts on four different exposure to the carboxy-terminal 105 amino acids of APP receptors designated as EP1 to EP4 EP1 (). Incubation of cultured microglia with Aβ and EP2 receptors have been detected in cultured microglia, increased IL-1, IL-6, TNF-α MIP-1α and MCP-1 in a dose- while EP3 receptors are also present in activated microglia in dependent manner ( vivo ). Microglial EP2 receptors inhibit phagocytosis and enhance neurotoxic activities of microglia Altogether, Aβ stimulated produc- ). PGE2 may also act on the neuronal EP2 tion of interleukins and other cytokines and chemokines and receptor, which is involved in apoptosis, although investiga- their feedback activation of APP production or BACE1 tions of the role of EP2 activation on neuronal cell death have ) may establish a self-perpetuating, vicious yielded conflicting results and somewhat suggested a neuro- cycle. A second general category of cytokine action is mani- protective role of neuronal EP2 stimulation under several fested by inhibitory, anti-inflammatory cytokines such as IL-1 pathophysiological circumstances ( receptor antagonist (IL-1Ra), IL-4, IL-10 and TGF-β. Some of these are reportedly elevated in AD, consistent with induction of This is further exemplified in a homeostatic mechanisms in neuroinflammation recent report where the knockout of EP2 in a double transgenic (APP/PS1) mouse led to decreased evidence of oxidative stress use of anti-inflammatory cytokines such as IL-4 and TGF-β and decreased Aβ production, associated with lower levels of could be beneficial, because they are able to inhibit CD40 and BACE (). In conclusion, the neuronal and glial class II MHC by restricting their expression and activity secretion of PGE2 may impair the phagocytotic clearance of Aβ ). However, an overexpression of TGF-β by binding to the microglia EP2 receptor and enhancing in transgenic mice leads to changes in the microvasculature, microglial toxicity. However the role of PGE2 in neurodegenera- including age related amyloid deposition tion may be far more complex due to the presence of other EP reflecting the multi-functional nature of many cytokines.
receptor subtypes on microglial cells and the effects of PGE2 on In addition to the above described evidence from the analysis of other cell types. Neuronal death elicited by excitotoxins is human brain tissue, cell culture and transgenic animal studies, elevated in transgenic animals with high expression of COX-2, an association of AD with several polymorphisms of proin- suggesting that the COX-2 expression may further interact with flammatory genes has been described, including IL-1 ( other pathogenetic mechanisms ), IL-6 ), TNF-α It should be noted that some aspects of microglial function and α1-antichymotrypsin, an acute may be beneficial, since activated microglia are able to reduce phase protein ). However, none of the Aβ accumulation by increasing its phagocytosis, clearance various members of the interleukin cytokine family that are and degradation ). Thus, associated with AD actually map to chromosomal regions with secreted Aβ1–40 and Aβ1–42 peptides are constitutively degrad- evidence of genetic linkage ). Thus, ed by the insulin degrading enzyme (IDE), a metalloprotease although inflammation and the up-regulation of inflammatory released by microglia and other neural cells. Finally, microglia mediators like the interleukins are regularly observed in AD can also secrete several trophic factors, such as the glia- brain, it appears less likely that variation at the genomic level of derived neurotrophic factor (GDNF), which exert a well these proteins makes a large contribution to AD risk in general.
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