Progress in Neurobiology 92 (2010) 293–315

Microglia and neuroprotection: From in vitro studies to therapeutic applications

Elisabetta Polazzi, Barbara Monti *

Department of Biology, University of Bologna, Italy

Contents

1. Microglia: origin and role in brain physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

1.1. Morphological and functional characterization of microglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

1.2. Physiological functions of microglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

1.3. Origin of microglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

2. Microglia: role in neuropathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

2.1. Microglial involvement in neurodegenerative diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

2.1.1. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

2.1.2. Parkinson’s disease and synucleopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

2.1.3. Amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

2.1.4. Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

2.2. Microglia and neuroinflammation: general anti-inflammatory agents as a treatment for neuropathologies. . . . . . . . . . . . . . . . . . . . 298

2.2.1. Use of anti-inflammatory drugs in Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

2.2.2. Use of anti-inflammatory drugs in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

A R T I C L E I N F O

Article history:

Received 12 March 2010

Received in revised form 21 June 2010

Accepted 22 June 2010

Keywords:

Microglia

Neurodegenerative diseases

Neuroprotection

In vitro models

Gene therapy

A B S T R A C T

Microglia are the main immune cells in the brain, playing a role in both physiological and pathological

conditions. Microglial involvement in neurodegenerative diseases is well-established, being microglial

activation and neuroinflammation common features of these neuropathologies. Microglial activation

has been considered harmful for neurons, but inflammatory state is not only associated with neurotoxic

consequences, but also with neuroprotective effects, such as phagocytosis of dead neurons and clearance

of debris. This brought to the idea of protective autoimmunity in the brain and to devise

immunomodulatory therapies, aimed to specifically increase neuroprotective aspects of microglia.

During the last years, several data supported the intrinsic neuroprotective function of microglia through

the release of neuroprotective molecules. These data led to change the traditional view of microglia in

neurodegenerative diseases: from the idea that these cells play an detrimental role for neurons due to a

gain of their inflammatory function, to the proposal of a loss of microglial neuroprotective function as a

causing factor in neuropathologies. This ‘‘microglial dysfunction hypothesis’’ points at the importance of

understanding the mechanisms of microglial-mediated neuroprotection to develop new therapies for

neurodegenerative diseases. In vitro models are very important to clarify the basic mechanisms of

microglial-mediated neuroprotection, mainly for the identification of potentially effective neuropro-

tective molecules, and to design new approaches in a gene therapy set-up. Microglia could act as both a

target and a vehicle for CNS gene delivery of neuroprotective factors, endogenously produced by

microglia in physiological conditions, thus strengthening the microglial neuroprotective phenotype,

even in a pathological situation.

� 2010 Elsevier Ltd. All rights reserved.

Abbreviations: Abeta, beta-amyloid; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; ApoE, apolipoprotein E; APP, amyloid precursor protein; BBB, blood–brain

barrier; BDNF, brain-derived neurotrophic factor; BM, bone marrow; BMT, bone marrow transplantation; HD, Huntington’s disease; CNTF, ciliary neurotrophic factor; COX,

cyclooxygenase; CSF, colony stimulating factor; DLB, Lewy body disease; GA, glatiramer acetate; Cop-1, Copolymer 1; GDNF, glial-derived neurotrophic factor; IGF-1, insulin-

like growth factor 1; IL, interleukin; LB, Lewy bodies; LPS, lipopolysaccharide; MCI, mild cognitive impairment; M-CSFR, macrophage colony-stimulating factor receptor;

MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MSA, multiple system atrophy; NDD, neurodegenerative disease; NFT, neurofibrillary tangles;

Contents lists available at ScienceDirect

Progress in Neurobiology

journa l homepage: www.e lsev ier .com/ locate /pneurobio

NGF, nerve growth factor; NO, nitric oxide; NSAID, non-steroidal anti-inflammatory drug; OGD, oxygen glucose deprivation; PD, Parkinson’s disease; PGn, plasminogen;

PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SN, substantia nigra; SOD1, superoxide dismutase 1; TGF, transforming growth factor; TNF,

tumor necrosis factor; WT, wild-type.

* Corresponding author at: Department of Biology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy. Tel.: +39 051 2094134; fax: +39 051 2094286.

E-mail address: b.monti@unibo.it (B. Monti).

0301-0082/$ – see front matter � 2010 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pneurobio.2010.06.009

E. Polazzi, B. Monti / Progress in Neurobiology 92 (2010) 293–315294

2.2.3. Use of anti-inflammatory drugs in amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

2.2.4. Anti-inflammatory drugs: conclusive remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

2.3. Immunomodulatory therapies for neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

2.3.1. Vaccination-based therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

2.3.2. Immuno-modulatory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

3. Microglia–neuronal interactions: from neurodegeneration to neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

3.1. The microglial role in neurodegenerative diseases: from the ‘‘neuro-inflammatory’’ to the ‘‘microglial-dysfunction’’ hypothesis. . . 300

3.1.1. The ‘‘neuro-inflammatory hypothesis’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

3.1.2. From the ‘‘non-cell-autonomous hypothesis’’ to the ‘‘neuro-neglect hypothesis’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

3.1.3. The ‘‘microglial-dysfunction hypothesis’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

3.2. Neuroprotective functions of microglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

3.2.1. In vivo evidences of microglial-mediated neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

3.2.2. In vitro identification of microglial-secreted neuroprotective molecules: towards a therapeutic application. . . . . . . . . . . . 303

4. Gene delivery of neuroprotective factors to the CNS through microglia: towards a therapeutic approach for NDDs . . . . . . . . . . . . . . . . . . 304

4.1. Gene delivery of neuroprotective factors to the CNS: basic remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

4.2. Identification of new neuroprotective factors: from in vitro studies to a therapeutic approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

4.3. Microglia as a target and a vehicle for CNS gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

1. Microglia: origin and role in brain physiology

1.1. Morphological and functional characterization of microglia

Microglia are the unique population of CNS resident immunecells. Their principal function is the quickly response to thepresence of pathogens and to brain damage. They are distributedthroughout the CNS, represent around 5–20% of the adult braincells, depending on the species, and constitute approximately 20%of glial cell population. Interestingly the density and themorphology of microglia are region-specific, being more abundantin the gray, than in the white matter (Lawson et al., 1990). Thisstrongly suggests that these differences might be related to amicroglial functional heterogeneity, even if little is known aboutthe nature of this heterogeneity among and within brain regions. Ingeneral, parenchymal microglia are highly ramified and aredistinct from other microglial cells, more macrophage-like, suchas those found in perivascular or meningeal locations (Davoustet al., 2008; Kida et al., 1993). The structural organization, theproximity to the vasculature and the biochemical environmentcould confer specific features to microglial cells (Adams et al.,2007; Binstadt et al., 2006; de Haas et al., 2008; Perry et al., 1992;Ransohoff and Perry, 2009). In addition, subsets of microglia mighthave different activities, without being distinguishable morpho-logically. Although it is established that substances released fromneurons can influence, at least in culture, microglial activity andrelease of different substances (Liang et al., 2010; Polazzi et al.,2001; Polazzi and Contestabile, 2006), there are only few reportsthat indicate constitutive or inducible diversity of microglia in CNSregions in physiological conditions. Expression of different RNA forcytokines and receptors has been demonstrated in microglial cellsderived from hippocampus, diencephalon, tegmentum, cerebellumand cerebral cortex (Sriram et al., 2006; Ren et al., 1999).Neurotrophin expression is selectively found in microglia fromthe cerebral cortex, globus pallidus and medulla, but not fromother CNS tissues (Elkabes et al., 1996). The existence of two typesof microglia has been observed in rat mixed glial cultures on thebasis of morphology and inflammatory response (Kuwabara et al.,2003) and different markers for reactive microgliosis have beenused to define subpopulations of microglia that respond to minorCNS injury (Wirenfeldt et al., 2005).

In addition to functional differences, microglial morphology hasbeen also reported to vary, depending on brain location (Lawsonet al., 1990). In the rat brain, microglial cells in the grey matter

were characterized by round stomata and branched processes,while, in the white matter, they displayed oval somata and fewprocesses, thus suggesting that active substances from cells of thegrey matter could stimulate the growth of microglial processes(McKay et al., 2007; Savchenko et al., 2000). Interestingly, it hasbeen demonstrated that macrophages showed stronger adhesionto brain tissues from gray matter than to tissues from the whitematter (Brown and Perry, 1998), thus pointing at adhesionmolecules differentially expressed by neuronal cells as key factorsin neuron–microglia interactions. These data suggest that, whenmicroglial precursors enter the CNS during development, theydifferentially interact with neurons via adhesion molecules, thuscontributing to the heterogeneity in microglial distributionobserved in the adult, healthy brain (Brown and Perry, 1998).

1.2. Physiological functions of microglia

Microglia are perhaps the most mysterious cells of the immunesystem and the immunologists nowadays are not completelyfamiliar with their physiology. In fact, microglia form a uniquepopulation of resident macrophages with several peculiarities thatdistinguish them from other populations of macrophages. Majorfeatures of microglia are their highly ramified morphology andplasticity that allow them to supervise the extracellular CNSparenchyma and to be quickly activated in response to pathologi-cal conditions, thus exerting typical macrophagic functions, suchas phagocytosis (Napoli and Neumann, 2009; Neumann et al.,2009), secretion of proinflammatory cytokines (Banati et al., 1993;Gehrmann et al., 1995; Minghetti and Levi, 1998) and antigenpresentation (Aloisi, 2001; Beauvillain et al., 2008). The studies onmicroglial biology have generally established that microglial cellsexert crucial physiological function during brain development, byinducing apoptosis of specific neuronal subpopulation, thereforecontributing to a numerical control of neuronal cells (Ashwell,1990; Egensperger et al., 1996; Marin-Teva et al., 2004; Streit,2001). In addition, during brain development, microglia supportthe synaptogenesis through the local synthesis of neurotrophicfactors (Aarum et al., 2003; Elkabes et al., 1996; Walton et al., 2006)and the regulation of synaptic transmission and remodeling(Fourgeaud and Boulanger, 2007; Jonakait et al., 1996, 2000;Stevens et al., 2007). As it will be described in a more detailed wayin the next paragraphs, microglial activation is also criticallyinvolved in various injuries and neurodegenerative diseases,including Alzheimer’s disease (AD), amyotrophic lateral sclerosis

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(ALS) and Parkinson’s disease (PD) (Boillee et al., 2006; Long-Smithet al., 2009; Mount et al., 2007; Schwab and McGeer, 2008).However, ablation of reactive microglia in both ALS and AD models(Butovsky et al., 2007; Gowing et al., 2008; Grathwohl et al., 2009)has no effect on neuronal degeneneration. It is clear that a betterunderstanding of the role of microglia and, in general, ofinflammation in many neurodegenerative diseases is required todevelop treatments to prevent neuronal damage and to improverepair. Not only the role of microglia in brain injury is stillcontroversial, but also little information is available on microglialcells in the adult healthy brain. Moreover, the nature and thefunction of the interactions between microglia and neuronalcircuits are incompletely understood. However, recently anelegant in vivo imaging study demonstrated that, in the absenceof pathological insults, non-activated ‘‘resting’’ microglia are farfrom dormant and dynamically extend and retract their processes,thus surveying the microenvironment and the synapse (Wakeet al., 2009). This clearly indicates, for the first time, that microglialcells in the normal brain parenchyma possess not only a function ofresting-resident macrophages, but also take part in the mainte-nance of functional state of synapses.

1.3. Origin of microglia

Today, the origin of microglia still remains highly debated andthe precise origin of this cell lineage remains to be fullyestablished. The two most important hypotheses on microgliaorigin are the ‘‘neuroectodermal’’ and the ‘‘myeloid-monocytic’’derivation. The latter one has now been widely accepted and it isbelieved that, unlike astrocytes, oligodendrocytes and neurons,which are derived from neuroectoderm, both perivascular andparenchymal microglial cells derive from myeloid progenitors (forreview see Chan et al., 2007). The ‘‘neuroectodermal hypothesis’’for microglial origin was supported by studies on identification ofmicroglial markers during brain development, on germinal matrixof the CNS or in the neuroectoderm (Hao et al., 1991; Hutchinset al., 1990). Another series of experiments, based on cell cultures,suggested that microglia and astrocytes derived from a commonprogenitor cell (Eglitis and Mezey, 1997; Fedoroff et al., 1997;Richardson et al., 1993). The ‘‘myeloid-monocytic hypothesis’’,states that resident microglia, as well as the other tissue residentmacrophages, derived from circulating blood monocytes, duringthe late embryonic life and post-natally. However, the data onmicroglia in the developing brain before vascularization (Wanget al., 1996) and the formation of macrophages in the neuroepi-telium from hematopoietic precursors different from monocytes(Takahashi and Naito, 1993), together with the phenotypicaldifferences in the lineage of mononuclear phagocytes between theembryonic–fetal stage and the neonatal–adult period (Faust et al.,1997; Naito et al., 1996; Takahashi, 2001), indicate that prenatallymicroglia may be generated from mesodermal progenitors,different from the ones of monocytes.

Andjelkovic et al. (1998) suggested the existence of twodifferent types of microglial myeloid progenitors: (i) one popula-tion, present during fetal development, mainly derived frommyeloid/mesenchymal, not from monocytes, and differentiatedinto parenchymal microglia, persisting throughout the whole adultlife; (ii) the other population, known as ‘‘ameboid microglia’’,derived from circulating monocytes and invaded the CNSpredominantly during perinatal and postnatal development. Thepossibility that these cells differentiate in parenchymal microgliais controversial (for review see Davoust et al., 2008; Soulet andRivest, 2008). There are also differences in the age of microglialcolonization among the species; for example, in rodents, it takesplace during the early postnatal period, while in humans beforebirth. Furthermore, it is largely accepted that a large number of

microglial cells are generated after birth and after the formation ofthe blood brain barrier (BBB). This raises the question of howmicroglia population is maintained in the adulthood. In adultphysiological conditions, a small percentage of perivascularmicroglia are re-populated by circulating precursors derived frombone marrow (BM). A previous hypothesis postulated that adultmicroglia are renewed through self-replication or by division ofprogenitor cells, already present in the brain. On the contrary,recent studies demonstrated that BM stem cells populate the CNSand, most importantly, differentiate into parenchymal microglia,as well as perivascular microglia (Simard and Rivest, 2004). Whilethe concept of physiologic infiltration of BM-derived microglia inthe intact CNS is somehow disputed, there is no doubt that theseprecursors can populate the brain during injuries and diseases(Beck et al., 2003; Eglitis and Mezey, 1997; Flugel et al., 2001;Ladeby et al., 2005; Lassmann and Hickey, 1993; Priller et al., 2001;Soulet and Rivest, 2008; Theele and Streit, 1993; Vitry et al., 2003).As a concluding remark, the identification of the tissue of originand lineage of resident parenchymal microglia will have significantimportance for therapeutic use of these cells since they represent anew vehicle for delivering key molecules able to improve repair ininjured nervous system (see below).

2. Microglia: role in neuropathology

2.1. Microglial involvement in neurodegenerative diseases

Virtually, every neurological disorder leads to inflammation,with activation of resident microglia, accompanied by an increasein number and change in phenotype of glial cells, a phenomenongenerally termed ‘‘reactive gliosis’’. Acute neurodegenerativediseases, such as stroke, hypoxia, and trauma, compromiseneuronal survival and indirectly trigger neuroinflammation, asmicroglia become activated in response to the insult itself, thusadopting a phagocytic phenotype and releasing inflammatorymediators, mainly cytokines and chemokines. This acute neuroin-flammatory response is generally beneficial to the CNS, since ittends to minimize further injury and it contributes to repair ofdamaged tissues (Kiefer et al., 1995; Kim et al., 2009a; Imai et al.,2007; Lalancette-Hebert et al., 2007; Lambertsen et al., 2009;Neumann et al., 2006; Madinier et al., 2009; Streit et al., 1998;Yanagisawa et al., 2008). In contrast, chronic neurodegenerativediseases, including Alzheimer’s disease (AD), Parkinson’s disease(PD), Huntington’s disease (HD), amyotrophic lateral sclerosis(ALS), tauopathies and multiple sclerosis (MS), are known to beassociated with chronic neuroinflammation, even if severaldifferences have been identified among these pathologies. Chronicneuroinflammation is a long-standing and often self-perpetuatingresponse that persists long after an initial injury or insult eithergenetical or environmental in nature. It is generally characterizedby a long-standing activation of microglia and subsequentsustained release of inflammatory mediators leading to increasedoxidative and nitrosative stress. This, in turn, works to perpetuatethe inflammatory cycle, activating additional microglia, promotingtheir proliferation and resulting in a further release of inflamma-tory factors. Besides playing a protective role as acute neuroin-flammation does, chronic neuroinflammation is most oftenconsidered detrimental and damaging to nervous tissue. Thus,whether neuroinflammation has beneficial or harmful outcomes inthe brain may depend critically on the duration of the inflamma-tory response and on the kind of microglial activation (reviewed byFrank-Cannon et al., 2009).

2.1.1. Alzheimer’s disease

The involvement of microglia in AD, the most commonneurodegenerative disease characterized by loss of cognitive skills

E. Polazzi, B. Monti / Progress in Neurobiology 92 (2010) 293–315296

and progressive dementia, is well-established since microglial cellshave been found associated to the amyloid plaques in AD brain, aswell as in primate and transgenic mouse models of the disease(Bornemann et al., 2001; Frautschy et al., 1998; Leung et al., 2009;McGeer et al., 1987; Stalder et al., 1999). The pathological hallmarkof AD is the presence of numerous senile plaques throughout thehippocampus and the cerebral cortex, associated with degenerat-ing axons, neurofibrillary tangles and gliosis. The core of the senileplaque is primarily composed of beta-amyloid peptides (Abeta),which are proteolytically derived from the membrane-boundamyloid precursor protein (APP) and form fibrils of beta-pleatedsheets. According to the ‘‘amyloid hypothesis’’, accumulation ofAbeta in the brain is the primary player driving AD pathogenesis.Other pathologic hallmarks, including formation of neurofibrillarytangles containing hyperphosphorylated tau protein, are proposedto derive from the Abeta pathology (reviewed by Hardy and Selko,2002). Notwithstanding the huge amount of literature in the field,the exact role of microglia in AD is still unclear, as it remainsuncertain whether microglia contribute to formation of theamyloid fibrils of plaques or whether they are attracted by andreact with them in a macrophage-phagocytic way (Cummingset al., 1992; Davis et al., 1992; reviewed by D’Andrea et al., 2004;Itagaki et al., 1989; Ohgami et al., 1991). From the beginning, it wasclear that a strong neuroinflammatory response was related to AD(Rogers et al., 1988), as demonstrated by the attachment ofcomplement proteins to damaged tissue and by the activation ofcells associated with the immune system in AD brain, evaluated bythe presence of reactive microglia and by the infiltration of T-cells(McGeer et al., 1989). However, it is still unclear whether Abetapeptides activate the inflammatory reaction in microglial cells(Griffin et al., 2006; Klegeris et al., 1994; Korotzer et al., 1993;Lindberg et al., 2005; Maier et al., 2008; McDonald et al., 1997;Meda et al., 1995, 1999; Mrak et al., 1995) or it is the inflammationthat drives amyloidogenesis (Vandenabeele and Fiers, 1991).Interestingly, microglial activation by Abeta peptides is negativelymodulated by apolipoprotein (APO) E3, but not APOE4, a variantassociated with an increased risk for AD (Barger and Harmon,1997). By analyzing APOE genotyped AD brains, it has beenobserved that the APOE gene product represents an importantdeterminant of microglial activity in AD, by down regulating glialactivation and facilitating the clearance of Abeta by microglia(Egensperger et al., 1998; Jiang et al., 2008; Lynch et al., 2001).Until now, it is not clear whether microglia are a source of Abeta inAD (Bitting et al., 1996; Frackowiak et al., 1992; Haass et al., 1991),while it is known that amyloidogenic processing of APP mainlytakes place in neurons and astrocytes (LeBlanc et al., 1997).Although microglia have been shown to express the APP, it isunlikely that microglia release amyloid fibrils in the extracellularspace. Nevertheless, the mechanism of formation of the depositsmay be related to the failure of a clearance mechanism that wouldnormally remove the protein, as reviewed by Napoli and Neumann(2009). Because microglia are phagocytic cells, it has beensuggested that they may function as plaque-attacking scavengercells (Ard et al., 1996; Bornemann et al., 2001; Chung et al., 1999;Huang et al., 1999; Paresce et al., 1996, 1997; Shaffer et al., 1995).Abeta fibrils also act as an immune signal to stimulate microglialphagocytosis (Kopec and Carroll, 1998; Mandrekar et al., 2009). Ingeneral, microglia become attracted towards site of injury byfactors released from damaged neurons, as well as by oligomersand protofibrils. Decreased microglial accumulation in AD brainresults in a increased Abeta deposition, particularly in and aroundblood vessels. These findings indicate that microglia play aprotective role in AD by mediating Abeta clearance (Britschgiand Wyss-Coray, 2007). Interestingly, the phagocytic properties ofmicroglial cells are very important in the therapeutic approach ofvaccination for AD, as described in Section 2.3.1. The fact that

microglial activation is not detrimental in AD has been proposedfor the first time by DiCarlo et al. (2001), who observed thatmicroglial activation in an AD model increases the clearance ofAbeta. More recently, it has been observed that activation ofmicroglia is necessary for Abeta clearance (Herber et al., 2007). Thisconcept has been recently supported through the nearly completeablation of reactive microglia, as it has been observed that neitheramyloid plaque formation and maintenance nor amyloid-associ-ated neuritic dystrophy depended on the presence of activatedmicroglia (Butovsky et al., 2007; Grathwohl et al., 2009). This studydemonstrated the presence of newly recruited macrophages,derived from the bone marrow stem cells, able to prevent theformation or eliminate the presence of amyloid deposits in ADmice. Therapeutic strategies aiming to improve their recruitmentcould potentially lead to a new powerful tool for clearance of toxicsenile plaques (Hawkes and McLaurin, 2009; Simard et al., 2006;Simard and Rivest, 2004, 2006). Further supporting this idea, it hasbeen demonstrated that, although early microglial recruitmentpromotes Abeta clearance and is neuroprotective in AD, as diseaseprogresses, proinflammatory cytokines produced in response toAbeta deposition down-regulate genes involved in Abeta clearanceand promote Abeta accumulation, therefore contributing toneurodegeneration, suggesting a dichotomous microglial role inAD (Frank-Cannon et al., 2009; Hickman et al., 2008). In AD brain,microglia are also associated with neurofibrillary tangles (NFT)(Cras et al., 1991). Activated microglia and astrocytes have beenimplicated in the progressive formation and evolution of NFT in AD(Sheng et al., 1997). In particular, activated microglia can induceaccumulation of the aggregation-prone tau molecules in neuritesand microglial activation also preceded tangle formation (Gorlovoyet al., 2009). In contrast with AD, microgliosis seems to be an earlyevent in neurodegenerative tauopathies as abrogation of tau-induced microglial activation could retard progression of thesedisorders (Yoshiyama et al., 2007).

2.1.2. Parkinson’s disease and synucleopathies

Parkinson’s disease (PD) is a common neurodegenerativedisorder characterized by the progressive loss of the dopaminergicneurons in the substantia nigra pars compacta (SNpc). Theinflammatory process in PD is characterized by activation ofresident microglia, with few reactive astrocytes (Orr et al., 2002;Teismann et al., 2003; Vila et al., 2001). The absence of reactiveastrocytosis in PD contrasts with what happens in virtually any otherneurological disorder and may indicate that the inflammatoryprocess in PD is a rather unique phenomenon (Mirza et al., 2000).Reactive microglia have been identified close to Lewy bodies (LB) inthe SN of both idiopathic and genetic cases of PD and PD dementia, aswell as in animal models of the disease (Członkowska et al., 1996;Gao et al., 2002a,b, 2003; Le et al., 2001; Matsuura et al., 1997;McGeer et al., 1988a,b, 2003; Orr et al., 2005; Sherer et al., 2003; Wuet al., 2005), even if their association with LB is still not clear(Rozemuller et al., 2000). It is also unclear whether microglialactivation precedes and induces neuronal damage or damagedneurons release factors, which in turn activate microglia. In theMPTP mouse model of PD, it was observed a robust gliosis in the SN

preceding or paralleling MPTP-induced dopaminergic neurodegen-eration (Liberatore et al., 1999). This neurotoxin stimulates atransient increase in the rate of macrophage infiltration into thebrain, concomitant with the onset of microglia activation, suggestingthat peripherally derived microglia may play a role in MPTP-induceddegeneration (Kokovay and Cunningham, 2005). However, the roleof alpha-synuclein (a major component of Lewy bodies that cancause neurodegeneration when aggregated) in microglial activationseems to be prominent, as damaged nigral neurons releaseaggregated alpha-synuclein into SN, which activates microglia withproduction of proinflammatory mediators, thereby leading to

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persistent and progressive nigral neurodegeneration in PD (Rey-nolds et al., 2008a; Zhang et al., 2005). Starting from the idea thatmicroglial activation is a crucial event even in PD pathogenesis, it hasbeen developed a model for PD in which rat brain treatment with theinflammogen lipopolysaccharide (LPS) triggers a rapid activation ofmicroglia, followed by a delayed and gradual loss of nigraldopaminergic neurons (Gao et al., 2002b). This model, being purelyinflammation-driven, has to be mainly considered an addition to thecurrently available animal PD models, but it further supports the roleof microglial activation in PD ethiopathology (reviewed by Whitton,2007). LPS-injection in SN triggers the release of inflammatoryfactors by microglia, determining a paracrine activation of astro-cytes, which in turn enhances their production of toxic mediators,such as ROS. These factors are suggested to act additively orsynergistically with neurotoxic factors produced by microglia (Saijoet al., 2009). Nevertheless, the activation scheme of microglia in PDmodels seems to be rather peculiar, as dopaminergic neuronal deathper se does not induce secretion of these proinflammatory cytokines,but an additional stimulus is required to stimulate proinflammatorycytokine production. Therefore, the production of proinflammatorycytokines from ‘‘primed’’ microglia may modulate the diseaseprogression (Depino et al., 2003; Mangano and Hayley, 2009).However, contrasting results on microglial activation in PD-likeneurodegeneration have been obtained in the different in vivo

models of PD (Hurley et al., 2003) and even in PD patients (Banatiet al., 1998). From these data, it appeared that, while microgliaresponded to alpha-synuclein deposition, a contributory or evencausative role for microglia in the neuronal loss associated with PDseems unlikely (Croisier et al., 2005) and neuroinflammation seemsto be a consequence of dopaminergic neuronal degeneration.Moreover, microglia activation can engage neighboring glial cellsin a cycle of autocrine and paracrine amplification of neurotoxicimmune products (Reynolds et al., 2008b). In conclusion, even if it isclear that microglia play an important role in PD (reviewed by Long-Smith et al., 2009), still remains the question of whether microglialactivation is a cause or a consequence of neuronal damage, ascontrasting results have been obtained even in similar models of thepathology (Henry et al., 2009; Marinova-Mutafchieva et al., 2009). Arecent observation from Sanchez-Guajardo et al. (2010) try toanswer this question by showing that, in an in vivo PD modelobtained by expressing alpha-synuclein at different levels, microgliapresent different activation profiles depending on the absence or thepresence of dopaminergic cell death, thus suggesting that microgliamay play different roles during disease progression (Frank-Cannonet al., 2009; Sanchez-Guajardo et al., 2010).

PD is the most common of a group of diseases characterized byalpha-synuclein pathologies, also including diffuse Lewy bodydisease (DLB) or multiple system atrophy (MSA). MSA is aneurodegenerative disorder that predominantly affects motor-related neuroanatomic structures. The prominent feature in MSA isthe degeneration of oligodendrocytes (Piao et al., 2003; Probst-Cousin et al., 1998). Activated microglia have been identified inMSA patients (Gerhard et al., 2003; Schwarz et al., 1998), in whichmicroglial activation is at least partly determined by oligoden-droglial alpha-synuclein in specific neuroanatomic systemsaffected in MSA (Ishizawa et al., 2004). Oligodendroglial over-expression of alpha-synuclein may induce neuroinflammationrelated to nitrosative stress, which is likely to contribute toneurodegeneration in MSA (Stefanova et al., 2007). It has also beendemonstrated a positive correlation between DLB, as well asfrontotemporal dementia, and microglial activation (Cagnin et al.,2004; Mackenzie, 2000a).

2.1.3. Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset motorneuron disease. A subset of cases is caused by mutations of

superoxide dismutase 1 (SOD1) gene, but most are sporadic (Rosenet al., 1993). The involvement of microglia in ALS has beenpostulated at the beginning of ‘90, by studying their activation inbrain and spinal cord tissues from patients and in in vivo models ofthe disease (Engelhardt and Appel, 1990; Hall et al., 1998; Wilmset al., 2001). Microgliosis in spinal cord tissue of mSOD1 mice isprimarily due to an expansion of resident microglia (Solomon et al.,2006). However, three distinct microglial populations have beendetected in ALS spinal cord: mature microglial cells, myeloidprecursor cells and macrophages (Gowing et al., 2008). Microgliaare not the only immune cells involved in ALS neuroinflammation,but also dendritic and myeloid cells are attracted in ALS spinal cordtissues by chemokines (Henkel et al., 2004, 2006, 2009). It has beenshown that microglial activation correlates with disease progres-sion in a mouse model of familial ALS, leading to the idea thatimmune-inflammatory mechanisms could contribute to thedisease progression (Alexianu et al., 2001). The causative role ofneuro-inflammation in ALS is also indicated by the fact thatminocycline, as well as other anti-inflammatory drugs, protectmice from loss of motor neurons and extend survival in the ALSmice models (Festoff et al., 2006; Kriz et al., 2002, 2003; Van DenBosch et al., 2002; West et al., 2004). However, it is still not clearwhich is the role of microglia in neuro-inflammation and whethermicroglia activation is a cause or a consequence of motor neurondegeneration. In fact, by using selective gene inactivation indifferent cell types, it has been clearly demonstrated that there isan early phase of disease within motor neurons and a later phaselinked to the inflammatory response of microglia, thus indicatingthat microglial activation is a secondary event in the disease(Boillee et al., 2006). In agreement with this, it has been shown thatablation of proliferating microglia does not affect motor neurondegeneration in ALS mice, suggesting that proliferating microgliaare not central contributors to the degenerative process (Gowinget al., 2008). Therefore, the mechanisms that bring to microgliaactivation and neurodegeneration in ALS have still to be clarified.Recently, by transplanting wild-type microglia in mSOD1 mice, ithas been shown that WT microglia are less neurotoxic, slow downmotoneuron loss and prolong disease duration and survival,suggesting a possible ‘‘loss of function’’ role for microglia as aconsequence of SOD1 mutation (Beers et al., 2006). Anotherimportant issue to understand the role of microglia in ALSneurodegeneration is the cross-talk between microglia and othercells types, not only neurons, but also astrocytes and T-cells (Appelet al., 2010). In this respect, it has been demonstrated thatastrocytes, but not microglia or neurons, expressing ALS-linkedmutated SOD1, release factors selectively toxic to motor neurons(Nagai et al., 2007). This led to a ‘‘non-cell autonomous’’ hypothesisfor ALS. This hypothesis (Ilieva et al., 2009; Lobsiger and Cleveland,2007; Wang et al., 2009) states that the damage, induced bymutant SOD1 in astrocytes determines the timing of microglialactivation and infiltration, amplifying an inflammatory responsefrom microglia (including enhanced production of nitric oxide andpossibly of toxic cytokines), leading to further damage to the motorneurons and accelerated disease progression (Yamanaka et al.,2008). In addition, secreted SOD1 mutant proteins activatemicroglia (Kang and Rivest, 2007). Interestingly, not only glia,but also BM transplanted T-cells, with either a lack of or reductionin SOD1 expression, enhance motor neuron protection and slowdisease progression, supporting a role for glial/T-cell interactionsin modulating trophic/cytotoxic balance of glia (Beers et al., 2008).Accordingly, it has been demonstrated that, in ALS diseaseprogression, microglia undergo a significant change towards aneuroprotective phenotype, mediated by T-cells (Chiu et al., 2008,2009). In contrast, it has also been demonstrated that ROS, whichcertainly play a central role in ALS neuropathology, derive frommicroglia, indicating also a ‘‘gain of function’’ in microglia

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activation, as a causative factor in neurodegenerative disease(Boillee and Cleveland, 2008; Henkel et al., 2009). Furthermore,over-expression of mutant SOD1 in microglia, as well asextracellular mutant SOD1, enhanced microglial secretion of aneurotoxic cytokine and increased generation of ROS, inducingmicroglial-mediated motor neuron injury (Liu et al., 2009; Zhaoet al., 2010). Considering the above-presented data altogether, therole of microglia in ALS seems to derive from both a loss ofmicroglial neuroprotective function (Beers et al., 2006, 2008;Boillee et al., 2006; Chiu et al., 2008, 2009; Gowing et al., 2008) anda gain of their neuroinflammatory function (Alexianu et al., 2001;Boillee and Cleveland, 2008; Henkel et al., 2009; Ilieva et al., 2009;Lobsiger and Cleveland, 2007; Yamanaka et al., 2008; Wang et al.,2009; Weydt et al., 2004), probably depending on the type, thedegree and the duration of the microglial activation state (Frank-Cannon et al., 2009). In this framework, the cross-talk between T-cell and microglia seems to be essential in ALS neuropathology, asin the early stages of disease the first response to injury, providedby the surrounding microglia and infiltrating T-cells, is neuropro-tective (Chiu et al., 2008, 2009), while at later stages thisneuroprotective response is transformed into a cytotoxic response(Appel et al., 2010), depending on their subtypes and activationstatus (Appel et al., 2009; Holmøy, 2008).

2.1.4. Huntington’s disease

Huntington’s disease (HD) is characterized by the progressivedeath of medium spiny, dopamine receptor bearing, striatalGABAergic neurons. Microglial activation in the areas of neuronalloss has recently been described in HD and presymptomatic HDpatients, even in the hypothalamus (Hsiao and Chern, 2010; Paveseet al., 2006; Politis et al., 2008; Sapp et al., 2001; Tai et al., 2007).There are increasing evidences that ‘‘non-cell-autonomous’’mechanisms play a central role in HD, in which neurodegenerationis strongly influenced by toxicity or mutant protein expression inboth neuronal and non-neuronal cells in the neighbourhood of thevulnerable neurons, especially the CNS glial cells (reviewed byLobsiger and Cleveland, 2007). Activated microglia, by releasingneurotoxic cytokines, may contribute to the pathologic process ofHD. In particular, mutant huntingtin fragments can perturbtranscriptional programs in microglia, thus implicating these cellsas potential modulators of neurodegeneration in HD (Giorginiet al., 2008). Interestingly, immune activation is detectable in bothCNS and PNS of HD patients. Monocytes, as well as macrophagesand microglia, from both HD mouse models and HD patientsexhibited abnormal immune activation, suggesting that immunedysfunction plays a role in this brain pathology (Bjorkqvist et al.,2008).

2.2. Microglia and neuroinflammation: general anti-inflammatory

agents as a treatment for neuropathologies

2.2.1. Use of anti-inflammatory drugs in Alzheimer’s disease

The proposal to use anti-inflammatory agents as a therapeuticapproach to AD started in the first ‘90s, only few years after the firstdemonstration of the involvement of inflammatory processes inAD (McGeer et al., 1990; McGeer and Rogers, 1992). As described inSection 2.1.1, a strong inflammatory response is associated withAD and it may be autotoxic to neurons, exacerbating thefundamental pathology in AD. Multiple epidemiological studiesindicate that patients taking anti-inflammatory drugs or sufferingfrom conditions, in which such drugs are routinely used, have adecreased risk of developing AD (McGeer and McGeer, 1995). Bystudying anti-inflammatory therapy for AD in both animal modelsand in patients, the basic mechanism was suggested to be throughthe suppression of microglial activation, but it is unclear whetherthese drugs act on brain Abeta levels, senile plaques or NFTs (Aisen,

2002; Mackenzie and Munoz, 1998; Mackenzie, 2000b; Netlandet al., 1998; Ralay Ranaivo et al., 2006; Yan et al., 2003; Wyss-Corayand Mucke, 2000; Weggen et al., 2001). It has been shown in pre-clinical models that non-steroidal anti-inflammatory drug (NSAID)therapies designed to influence the onset of AD should be initiatedin adults before age-associated inflammatory processes begin orearly in the disease course. Epidemiological studies confirm thatNSAIDs use in human AD needs to be initiated as early as possibleto prevent disease progression (Hauss-Wegrzyniak et al., 1999;Lim et al., 2000). These data receive support by the fact that NSAIDsare able to prevent, but not to reverse the neuronal cell cyclereentry, which marks vulnerable neuronal populations in AD, aswell as alterations in brain microglia without altering APPprocessing and steady-state Abeta levels (Varvel et al., 2009).Retrospective human epidemiological studies have identified long-term use of NSAIDs, such as aspirin, as protective against AD(Andersen et al., 1995; Kawas et al., 1997; Stewart et al., 1997).However, clinical trials have failed to demonstrate a similar benefit(Varvel et al., 2009). There is not yet any strong evidence fromcompleted randomized controlled trials that anti-inflammatorytreatment is beneficial. Large trials of NSAIDs in both preventionand treatment of AD, as well as mild cognitive impairment (MCI)have so far been disappointing (AD2000 Collaborative Group,2008; ADAPT Research Group, 2007; Aisen, 2002; Aisen et al., 2000,2003; de Jong et al., 2008; Green et al., 2009; in’t Veld et al., 1998;Skaper, 2007). All these results support the hypothesis that thechronic use of NSAIDs may be beneficial only in the normal brainby inhibiting the production of Abeta peptide. Once the Abetadeposition has started, NSAIDs are no longer effective and mayeven be detrimental because of their inhibiting activity of activatedmicroglia, which mediates Abeta clearance and activates compen-satory hippocampal neurogenesis (Imbimbo, 2009). Severalstudies are still in progress. Major issues of selection of patients,drug regimen and duration of treatment have to be resolved (Aisen,2002; Delanty and Vaughan, 1998; Etminan et al., 2003). Moreover,even if prolonged NSAIDs use may prevent the decline in cognitionassociated with aging, high dose NSAIDs use may be associatedwith a reversible impairment of cognition in the elderly. Inaddition, NSAIDs have multiple deleterious effects; therefore newanti-inflammatory drugs need to be developed (Karplus and Saag,1998; Najbauer et al., 2000; Pennisi, 1998; Warner and Mitchell,2004). To test the hypothesis that the benefit of NSAIDs use indiminishing the risk of AD is attributable to suppression of themicroglial response, the nitric oxide (NO)-releasing derivative ofthe NSAID flurbiprofen has been used. This drug is more effectivethan classical NSAIDs to reduce Abeta deposition in AD, butunexpectedly it activates microglia. This increased microgliaactivation may have caused the reduced Abeta levels in thetransgenic mice treated with the drug by phagocytosis andclearance of the Abeta deposits (Jantzen et al., 2002).

2.2.2. Use of anti-inflammatory drugs in Parkinson’s disease

Degeneration of dopaminergic neurons in the SN of the brain, ahallmark of PD, was significantly reduced, in in vivo models of PD, bynaloxone, an opioid receptor antagonist, as well as by minocycline,an approved tetracycline derivative that inhibits microglial activa-tion independently of its antimicrobial properties, and dexametha-sone, a potent anti-inflammatory drug that interferes with many ofthe features characterizing pro-inflammatory glial activation. Thesedrugs generally inhibit microglia activation and proliferation andprotect dopaminergic neurons from inflammatory damage, both in

vitro and in vivo (Castano et al., 2002; Liu et al., 2000; Lu et al., 2000;Tikka et al., 2001; Wu et al., 2002). Epidemiological studies indicatethat a regular use of NSAIDs, especially non-aspirin NSAIDs, exert aneuroprotective effect against PD (Wahner et al., 2007). However,recent meta-analysis studies on NSAIDs in PD revealed that these

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drugs do not seem to modify the risk of PD (Chen et al., 2005;Etminan et al., 2008; Samii et al., 2009). Very recently, in in vitro

models of neurodegeneration, it has been shown that hydrogensulfide-releasing NSAIDs attenuate neuroinflammation induced bymicroglial and astrocytic activation (Lee et al., 2010a). It isinteresting to note that hydrogen sulfide (H2S) is an essentialphysiological product in brain and that astrocytes are able toproduce by themselves this endogenous anti-inflammatory andneuroprotective agent (Lee et al., 2009).

2.2.3. Use of anti-inflammatory drugs in amyotrophic lateral sclerosis

Anti-inflammatory drugs have been tested in in vivo models ofALS, because of the role of secondary inflammation in ALSneurodegeneration. These agents, including minocycline, PPARagonists, COX-2 inhibitors and cannabinoid agonists, whenadministered at late presymptomatic or early symptomatic stages,delay the onset of motor neuron degeneration and slow downdisease progression in SOD1 mutant mice (Festoff et al., 2006; Kiaeiet al., 2005a,b,c; Kriz et al., 2002, 2003; Shoemaker et al., 2007; VanDen Bosch et al., 2002; West et al., 2004). However, meta-analysisstudies on the effect of either aspirin or non-aspirin NSAIDs did notreveal any reduction in the risk of ALS (Popat et al., 2007).Moreover, clinical trials have been performed to test anti-inflammatory agents in ALS patients and they showed that thesedrugs have not any beneficial effect or even could be harmful(Cudkowicz et al., 2006; Gordon et al., 2007). In particular, in trialwith ALS patients treated with anti-inflammatory drugs, it hasbeen observed that treatment with minocycline leads to a fasterprogression of the pathology, until to a greater mortality (Gordonet al., 2007), and thalidomide causes bradycardia in ALS patients,thus discouraging its use (Meyer et al., 2008).

2.2.4. Anti-inflammatory drugs: conclusive remarks

The above-presented data on NSAIDs in preventing orprotecting from neurodegeneration are becoming contrastingwith time, as these therapies often fail or even exacerbate thepathologies (Browne et al., 2006; Gordon et al., 2007; Meyer et al.,2008; Zandi and Breitner, 2001). This can be at least partiallyexplained by the fact that activated microglia can be bothneuroprotective, by phagocyting protein aggregates, cell debriesand apoptotic neurons, and neurotoxic, by releasing cytokines andROS. In fact, it has to be considered that defining what really‘‘activated microglia’’ mean and their physiopathological functionis not easy. Microglia are probably never in a ‘‘resting’’ state andseveral intermediate transitional states, based on function andmorphology, probably exist, leading to the idea of a ‘‘multifacedprofile’’ of microglia activation, as discussed by Lynch (2009). Thiswill explain why conventional anti-inflammatory drugs may fail.Another possible explanation of the NSAIDs failure comes fromstudies in transgenic mouse models for AD and ALS, in which it hasbeen demonstrated that ablation of microglia does not counteractneurodegeneration, thus demonstrating that microglia do notplay an active role in exacerbating these pathologies (Butovskyet al., 2007; Gowing et al., 2008; Grathwohl et al., 2009).Therefore, considering these data, anti-inflammatory therapyneed at least to be reconsidered and it has also to be re-assessedthe idea that neuroinflammation is completely detrimental.Moreover, it should be also considered that anti-inflammatorydrugs have multiple targets, thus leading to the hypothesis thatthey can work through pathways other than the inflammatoryones. Finally, the timing of the intervention should be in theearliest stages of the pathogenesis of neurodegenerative diseases,perhaps even before the first symptoms emerge. Discrepancybetween potentially positive results of retrospective epidemio-logical studies and negative results of short-term trials supportthis possibility.

2.3. Immunomodulatory therapies for neurodegenerative diseases

2.3.1. Vaccination-based therapies

The immune system, including microglia, is the major braindefense and repair mechanism, therefore it seemed realistic theuse of these capabilities to counteract neurodegeneration(Schwartz et al., 2009). This idea is well exemplified byvaccination-based therapies against various antigens of the CNS,which is a therapeutic approach of increasing interest in a varietyof neurological diseases, such as spinal cord injury, ischemicstroke, spongiform encephalopathy, as well as LBD and AD (Shenand Meri, 2003). Concerning chronic NDDs, vaccination has beentested in LBD models, through immunization with alpha-synucleinof transgenic mice over-expressing alpha-synuclein itself, thusleading to a reduction in neuronal accumulation of the aggregatedprotein (Masliah et al., 2005). Vaccination has been extensivelytested to counteract AD in animal models. Both strategies of activeimmunization with Abeta peptides or passive immunization withantibodies against Abeta reduced AD-like pathology, includingplaque burden, neuritic dystrophy, Tau pathology, microgliosis,and restored cognitive deficits in transgenic mice (Brody andHoltzman, 2008; Frenkel et al., 2000; Janus et al., 2000; Morganet al., 2000; Stalder et al., 1999; Wilcock et al., 2009; Younkin,2001). On the contrary, immunization with tau protein induced byitself histopathologic features of AD and tauopathies, as presenceof neurofibrillary tangle-like structures, axonal damage, gliosis andmononuclear cells infiltration in the CNS, accompanied byneurologic deficits, indicating potential dangers of using tau forimmunotherapy (Rosenmann et al., 2006).

The results on Abeta immunization trials appeared initiallypromising; however, they had to be halted because of theoccurrence of neuroinflammation (Gandy and Walker, 2004;Munch and Robinson, 2002). Knowledge gained from studies onAbeta immunotherapy is leading to optimization of new-genera-tion vaccines, targeting highly specific epitopes while reducingundesired side effects (Gelinas et al., 2004; Goni and Sigurdsson,2005; Monsonego et al., 2006). An unanswered question is howvaccination in peripheral tissues may reduce plaque burden in thebrain. A tentative explanation could be that the integrity of theblood–brain barrier (BBB) is compromised in AD model mice, but itis restored following immunization (Dickstein et al., 2006). Activeimmunization with Abeta or passive immunization with Abetaantibodies, as well as naturally occurring auto antibodies to Abetaor the infusion of Abeta-specific Th2 cells can lessen the severity ofAbeta-induced neuritic plaque pathology through the activation ofmicroglia (Cao et al., 2009; Dodel et al., 2003; Kellner et al., 2009;Lemere et al., 2006), as it has been observed that antibodies‘decorate’ plaques and trigger their clearance by microglial cells inthe brain (Bard et al., 2000; Schenk et al., 1999). It is interesting tonote that not only immunization with Abeta leads to its ingestionby microglia, but there is also marked microglial responsecompletely surrounding the remaining Abeta (Bacskai et al.,2001). Immune system response, including microglial activation istherefore necessary to remove Abeta following anti-Abeta anti-bodies treatment (Wilcock et al., 2004a,b). In this context, it has tobe underlined that in AD there is an Abeta-specific impairedadaptive immune response that may contribute to the neuropa-thology. In fact, transgenic mouse models for AD showed a reducedimmune responsiveness to Abeta, which can be overcome bylinking the Abeta epitopes to a carrier (Monsonego et al., 2001). Inhumans, it has been observed that T-cell reactivity to Abeta couldeither decrease or increase with aging and in patients with AD, dueto the fact that Abeta antigen is progressively deposited in the CNSwith age and in AD (Monsonego et al., 2003). Furthermore, thenature and magnitude of T-cell reactivity to Abeta in humans couldhave either beneficial or injurious effects for the host and may have

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important implications for Abeta vaccination strategies in AD.Moreover, anti-Abeta immunotherapy in amyloid-accumulatingtransgenic mice causes a complex series of changes in microglialmarkers, suggesting that at least two distinct activation states ofmacrophages do exist with different consequences for thesurrounding tissue (Morgan et al., 2005). These changes areconsistent with a shift in the microglial phenotype, from acondition associated with inflammation and ineffective in clearingAbeta deposits to one with reduced inflammation and capable ofclearing deposited amyloid, considering that efficiency of Abetaphagocytosis declines in most AD patients (Fiala et al., 2007;Morgan, 2006). Interestingly, Abeta DNA vaccines reduced Abetadeposits in AD model mice without detectable side effect, byincreasing microglial phagocytosis of beta-amyloid deposits as amajor clearance pathway (Okura et al., 2008).

2.3.2. Immuno-modulatory drugs

The balance between beneficial and deleterious immuneresponses is the most important issue to be resolved in order toreach an effective therapeutic approach for NDDs. In thisframework, it seems more and more interesting the use ofimmune-modulatory drugs, which are able to shift the immuneresponse towards neuroprotection. In particular, glatirameracetate (GA), also known as Copolymer 1 (Cop-1), is an approveddrug for the treatment of multiple sclerosis that can be used as atreatment for autoimmune diseases and as a therapeutic vaccinefor NDDs. It has been proposed that the protective effect of Cop-1vaccination is obtained through a controlled inflammatoryreaction and that the activity of Cop-1 derives from its abilityto serve as a ‘‘universal antigen’’ that weakly activates a widespectrum of self-reactive T-cells (Kipnis and Schwartz, 2002).Immunomodulatory drugs have been tested by themselves, aswell as together with other therapeutic approaches, includingvaccination. In particular, nasal vaccination with a proteasome-based adjuvant that is well tolerated in humans plus GA potentlydecreases Abeta plaques in an AD mouse model (Frenkel et al.,2005). This co-treatment activates microglia and determines adecrease in Abeta fibril deposition. Activation of microglia andclearing of Abeta occurred with the adjuvant alone, although to alesser degree. This is a very interesting approach, as it involvesclearing of Abeta through the utilization of compounds that havebeen safely tested on or are currently in use in humans (Frenkelet al., 2005). T-cell-based vaccination with GA resulted indecreased plaque formation, reduction of excitotoxicity andinduction of neurogenesis, as well as a reduction in cognitivedecline (Butovsky et al., 2006a,b; Schaeffer et al., 2009). Thevaccination apparently exerted its effect by causing a phenotypeswitch in brain microglia to dendritic-like cells producinginsulin-like growth factor 1 (IGF-1), a phenotype that counter-acted the adverse Abeta-induced effect. These results suggestthat dendritic-like microglia, whose recruitment is induced byGA from BM, might contribute significantly to the brain’sresistance to AD and argue against the use of anti-inflammatorydrugs (Avidan et al., 2004; Butovsky et al., 2006a,b, 2007;Schaeffer et al., 2009). GA vaccination has been also tested withpositive results in both acute and chronic motor neuron diseases,where it increases the survival of motor neurons by enhancingthe local immune response needed to combat destructive self-compounds associated with motor neuron death (Angelov et al.,2003), as well as on primary and secondary degeneration ofretinal ganglion cells (Blair et al., 2005). From these data, it hasbeen suggested that this type of vaccination could be a generaltreatment for most NDDS, including PD and glaucoma (Schwartz,2007; Tsai, 2007). However, contrasting results have beenobtained in an animal model of ALS, thus indicating the needof disease-specific approaches (Schwartz et al., 2008). Lenali-

domide is a potent immunomodulatory agent, with the ability todown-regulate pro-inflammatory cytokines and up-regulateanti-inflammatory cytokines. It has been reported that this drughas a neuroprotective effect in the ALS transgenic mouse modelswith treatments starting both before and at symptom onset ofdisease (Kiaei et al., 2006; Mosley and Gendelman, 2010;Neymotin et al., 2009). Together, these results support theconcept of ‘‘protective autoimmunity’’, showing that T-cell-based vaccination is protective irrespectively of the nature of thetoxic insult and suggesting that locally activated T-cells induce amicroglial phenotype that helps neurons survive (Hauben et al.,2000, 2001; Moalem et al., 1999). Which are the molecularmechanisms through which microglial cells may exert theirneuroprotective functions? Unfortunately, this aspect of micro-glial physiology is still unresolved, mainly for the difficulties tostudy the microglial response in vivo. This difficulty strengthensthe use of in vitro models to clarify the molecular mechanisms ofmicroglial-mediated neuroprotection. As considered in thefollowing chapters, the knowledge on the potentiality ofmicroglial neuroprotection that comes from in vitro studiesmay help in the identification of novel neuroprotectivemolecules.

3. Microglia–neuronal interactions: from neurodegenerationto neuroprotection

3.1. The microglial role in neurodegenerative diseases: from the

‘‘neuro-inflammatory’’ to the ‘‘microglial-dysfunction’’ hypothesis

3.1.1. The ‘‘neuro-inflammatory hypothesis’’

The role of microglial cells in neurodegenerative diseases isnot easily defined as very different, even contrasting, aspectshave to be taken into consideration. In fact, neuroinflammation,mainly mediated by microglial activation, but also by therecruitment of immune cells, is certainly a prominent featureof neuropathologies. Notwithstanding the differences amongthem, microglia play a quite similar role in most of thesepathologies, microglial activation and neuro-inflammation beinga common feature of these diseases. These observations led to theso-called ‘‘neuro-inflammatory hypothesis’’ of neurodegenera-tive diseases (Oken, 1995), which is described in Fig. 1, upperpanel. Several evidences supported this hypothesis: pathologicalstudies indicated an increased expression of inflammatoryfactors in affected brain areas from patients, as well as markersof glial activation (Cagnin et al., 2004; Cras et al., 1991;Mackenzie, 2000a; McGeer et al., 1987, 1988a,b, 1990; McGeerand Rogers, 1992); the association of inflammatory cytokinesDNA polymorphisms with the onset of neurodegenerativedisease (Bialecka et al., 2007; Du et al., 2000; McCusker et al.,2001; McGeer and McGeer, 2001; Wahner et al., 2007); dataobtained by both in vitro and in vivo models of neurodegenerativediseases revealed the involvement of inflammatory mechanisms(Bornemann et al., 2001; Członkowska et al., 1996; Frautschyet al., 1998; Leung et al., 2009; Matsuura et al., 1997; Sherer et al.,2003; Stalder et al., 1999; Wu et al., 2005). As a consequence ofthe neuro-inflammatory hypothesis, it has been evolved the ideathat the selective suppression of neurotoxic molecules producedby excessive glial activation will result in neuroprotection. Asdescribed in Section 2.3.1, preclinical and epidemiologicalstudies indicated a possible protective effect of NSAIDs. However,data on NSAIDs in preventing or protecting neurons fromdegeneration in NDDs are still contrasting (Browne et al.,2006; Gordon et al., 2007; Meyer et al., 2008; Zandi and Breitner,2001), thus suggesting that microglia could play a role differentfrom the one proposed by the neuro-inflammatory hypothesis inthese neuropathologies.

[(Fig._1)TD$FIG]

Fig. 1. Hypotheses on microglial role in neurodegenerative diseases (NDDs). In the upper panel, it has been illustrated the ‘‘neuroinflammatory hypothesis’’ for NDDs. As

described in Section 3.1.1 of the text, microglial activation and neuro-inflammation is a common feature of most NDDs and is supported by several data from both in vitro and

in vivo models of NDDs and from patiens. This hypothesis states that microglial-activation caused by either genetic or environmental stimuli determines the appearance of an

inflammatory state, with a microglial-release release of neurotoxic agents, such as cytokines, ROS and NO, which in turn leads to neuronal death. In the medial panel, the

‘‘non-cell-autonomous death hypothesis’’ for NDDs has been illustrated. As explained in Section 3.1.2, accordingly to hypothesis in NDDs there is a convergence of alterations

within multiple cell types, including neurons, astrocytes, microglia and T-cells, which is crucial to neuronal function and/or dysfunction. Three are the possible situations. In

part (a) of the panel, the stimulus is toxic only for neurons, which stimulate further damaging responses from glia. In part (b) of the panel, both neurons and glial cells are

damaged by the stimulus, but toxicity in glial cells results in an amplification of the initial damage to the vulnerable neurons. In the part (c) of the panel, toxicity within glia

could disturb normal glial function, thus becoming a primary source of neurotoxicity. The lower panel exemplifys the ‘‘microglial-dysfunction hypothesis’’ (Section 3.1.3), in

which it is proposed that, considering that microglia exerts an important function to protect neurons and the integrity of CNS and that this function gets lost in NDDs,

neurodegeneration mainly results from a ‘‘loss of microglia neurotrophic/neuroprotective functions’’. This neuroprotective role, as illustrated by the panel, is exerted though

the release of a broad panel of trophic factors, such as cytokines, antioxidants, neurotrophins and lysosomal enzymes, as described in Sections 3.2.1 and 3.2.2, and the

scavenging of toxic compounds, such as proteinaceous aggregates, and of cell debries released by the dying neurons, functions being impaired in aging and in NDDs.

E. Polazzi, B. Monti / Progress in Neurobiology 92 (2010) 293–315 301

3.1.2. From the ‘‘non-cell-autonomous hypothesis’’ to the ‘‘neuro-

neglect hypothesis’’

It is already clear that in neurodegenerative diseases there is aconvergence of alterations within multiple cell types, includingneurons, astrocytes, microglia and T-cells, which is crucial toneuronal function and/or dysfunction and implies a cross-talkamong the different brain cell types, whose normal function isaltered in neurodegenerative diseases (Appel et al., 2010).Examples of these interactions are that the glial immune functionsare strictly regulated by neurons through the release of soluble

factors and that astrocytes suppress microglial phagocytosisthough diffusible factors, thus contributing to proteinaceousaccumulation (DeWitt et al., 1998; Neumann, 2001). The impor-tance of different cell types in neurodegenerative diseases led tothe proposal of a ‘‘non-cell-autonomous’’ mechanism of neurode-generation, with a central role for brain non-neuronal cells ininducing neuronal death. This mechanism has been proposed inAD, PD, ALS and HD (Appel et al., 2010; Dawson, 2008; Di Giorgioet al., 2007; Hirsch and Hunot, 2009; Ilieva et al., 2009; Lobsigerand Cleveland, 2007; Nagai et al., 2007; Wang et al., 2009;

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Yamanaka et al., 2008). However, it remains to be clarified whetherthe role of glial cells in NDDs is necessary for, or contributes to, theneurodegenerative process. Three are the possible situations, asindicated by the central panel of the Fig. 1: (i) the toxic stimulusdetermines neuronal death, which in turn could stimulatedamaging responses from glia, even if glial cells are not directlydamaged by the toxic stimulus themselves; (ii) both neurons andglial cells are damaged by the stimulus, but toxicity in glial cellsresults in an alteration of the a normal glial response, amplifyinginitial damage to the vulnerable neurons; (iii) toxicity within gliacould disturb normal glial function, thus becoming a primarysource of neurotoxicity. The last two situations could be includedin the ‘‘neuro-neglect hypothesis’’, in which it is proposed that thetoxic stimulus, either genetic or environmental, determines analteration of the glial functions, mainly astrocytic, leading toinflammation and loss of neurosupporting role for glial cells untilneurodegeneration (Fuller et al., 2009). Neuronal injury arisingfrom these glial-induced insults can activate microglia with furtherover-expression of cytokines, mainly interleukin-1, thus producingfeedback amplification and self-propagation of cytokine cycle, aswell as a further attraction and activation of microglial cells (Griffinet al., 1998; Wegiel et al., 2001). This, in turn, could induceneuronal cell death, by releasing neurotoxic factors, such ascathepsin B (Combs et al., 2001; Gan et al., 2004; Kingham andPocock, 2001; Wu et al., 2000). This led to the theory of the‘‘cytokine cycle’’, as a possible explanation for progression ofneurodegenerative diseases. In this cycle, chronic activation of glialinflammatory processes, arising from genetic or environmentalinsults to neurons and accompanied by chronic elaboration ofneuroactive glia-derived cytokines and other proteins, drives achronic self-propagating cytokine cycle of cellular and molecularevents with neurodegenerative consequences (Griffin et al., 1998;Mrak and Griffin, 2005). Interestingly, this increase in thecytokines release is normally present in aging, thus suggesting asynergy between genetic and environmental risks (Mrak andGriffin, 2005). However, it has also to be considered that cytokinesare pleiotropic factors, promoting signals that either lead to celldeath or exert neuroprotective effects (Nagatsu and Sawada,2005). In particular, microglial activation can result in a beneficialor detrimental effect for neurons, depending on the releasedcytokines (Butovsky et al., 2005).

3.1.3. The ‘‘microglial-dysfunction hypothesis’’

According to the above-mentioned hypotheses, the glial,particularly microglial, role in neurodegenerative diseases isrestricted to a gain of their inflammatory functions, leading toneurodegeneration. However, a different explanation is gainingmomentum. In this view, it is proposed that neurodegenerationmainly results from a ‘‘loss of microglia neurotrophic/neuropro-tective functions’’. From the early ‘90s, it has been postulated theso-called ‘‘microglial-dysfunction hypothesis’’ (Fig. 1, lower panel),which states that microglia exerts an important function to protectneurons and the integrity of CNS and that this function gets lost inneurodegenerative diseases (Streit, 2004). In this framework, it isnow clear that microglial role is aimed at limiting the spreading ofneurodegeneration, as well as at promoting neuronal survival andreinforcing neuronal regeneration (Farfara et al., 2008; Gebicke-Haerter et al., 1996; Simard and Rivest, 2007). This role is exertedthough the release of trophic factors and the scavenging of toxiccompounds and of cell debris released by the dying neurons,functions, both modified in neuropathologies (Fiala et al., 2007;Napoli and Neumann, 2009; Turrin and Rivest, 2006; Vila et al.,2001). The physiological neuroprotective role of microglia ismainly mediated by the release of a broad panel of factors, such ascytokines, antioxidants, neurotrophins and lysosomal enzymes, asdescribed in Sections 3.2.1 and 3.2.2 (Garden and Moller, 2006;

Glanzer et al., 2007; Glezer et al., 2007; Polazzi and Contestabile,2002; Polazzi et al., 2001, 2009). Interestingly, it has been shownthat the phagocytic abilities of microglial cells, which are essentialfor the clearance of neuronal debris, as well as of proteinaceousaggregates, are altered in aging and impaired in neurodegenerativediseases (Marx et al., 1998; Rogers et al., 2002). This observationintroduces another important issue that has to be considered forthe ‘‘microglial-dysfunction hypothesis’’: the ‘‘senescence’’ ofmicroglia at the age of the onset of these pathologies. In humans,in non-human primates and in rodents, it has been observed that,during aging, there is a change in microglial activation, as well as intheir morphological features, leading to the hypothesis that agedmicroglia may become increasingly dysfunctional and thereforeless able to carry out in normal neuroprotective functions, withimportant effects on AD and other diseases typical of aged people.Therefore, microglial senescence, which may impair their neuron-sustaining functions and ultimately lead to neuronal cell death, canbe considered an important topic in the ‘‘microglial-dysfunctionhypothesis’’ (Flanary, 2005; Flanary et al., 2007; Lucin and Wyss-Coray, 2009; Streit, 2005, 2006; Streit and Xue, 2009). Startingfrom these observations, several drugs are now studied in order toincrease the neuroprotective functions of microglia or to shift themicroglial phenotype towards neuroprotection. Moreover, severalpharmacological treatments have been developed that use theimmunological properties of microglia for brain protection and/orrepair.

3.2. Neuroprotective functions of microglia

3.2.1. In vivo evidences of microglial-mediated neuroprotection

From the functional point of view, microglia could represent ahybrid between immune-competent cells and glial cells withneuronal-supporting functions. In this framework, recent studiesdemonstrated that resting microglia, dynamically extend andretract their processes actively surveying the microenvironmentand the functional status of synapses (Wake et al., 2009). Althoughthe nature and function of the interactions between microglia andneuronal circuits is only hypothesized, these studies clearlydemonstrated that microglia do not represent only ‘‘dormant’’resting macrophages, but actively exert neuroprotective actions onneuronal population. This surveying role is likely to be animportant factor in homeostasis maintenance during ‘‘micro-damage’’ that commonly occurs in the brain. It has been proposedthat, in the adult brain, microglia take part in synapse remodellingand, probably, in neurogenesis (Ekdahl et al., 2009). In vivo

evidences suggest microglial regulation of neurogenesis in thehippocampus (Battista et al., 2006; Ziv et al., 2006) and in the adultsubventricular zone, at least after stroke (Thored et al., 2009). In anin vitro model of neural stem cell co-culture with microglial cells ormicroglia-conditioned medium, microglia provided secretedfactor(s) essential for neurogenesis (Walton et al., 2006). Anyinsult to the CNS, including infection, trauma, or metabolicdysfunction cause microglia activation, which involves changesin morphology, cell number, surface receptor expression andproduction of growth factors and cytokines (Ransohoff and Perry,2009). Studies on the process of microglial activation indicatedthat activated microglia emerged from a resting state andunderwent morphological transformation from ramified to differ-ent activated forms, including amoeboid, rod-like, phagocytic andso on. But, what are the signals that lead to microglial activationand what are the phenotypes and functions of these cells?

In order to answer this crucial question, it has to be consideredthat microglia do not constitute a single, uniform cell population,but rather comprise a family of cells with diverse phenotypes,some beneficial and others detrimental (Butovsky et al., 2005,2006a,b; Schwartz et al., 2006, see Fig. 1). Accordingly, it has been

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suggested that, as macrophages, microglia can exhibit differentactivated phenotypes: M1 or an alternatively activated M2phenotype (Benoit et al., 2008; Geissmann et al., 2008). ActivatedM1 macrophages secrete great amounts of pro-inflammatorycytokines, principally tumor necrosis factor (TNF)-alpha andinterleukin (IL)-1beta, release ROS, such as superoxide radicals(O2�) and nitric oxide (NO), and reduce the release of neurotrophicfactors. M2 microglia show a more de-activated and anti-inflammatory phenotype. At least two different M2 sub-pheno-types have been distinguished, upon their gene expression profileand their different activating cytokines (Benoit et al., 2008;Geissmann et al., 2008). Since microglia are considered anomalousperipheral macrophages, their activation does not likely followthese precise pathways; nevertheless, the underlying concept ofmacrophage heterogeneity might apply to microglial responses.Recently, an in vitro study characterized microglial phenotypeunder specific pro-inflammatory and anti-inflammatory condi-tions, demonstrating that LPS or IFN-gamma induce a M1-likephenotype, while IL-10 or IL-4 differentiate microglia towards aM2-deactivated or M2-alternatively-activated phenotype respec-tively (Michelucci et al., 2009). These studies allow to a betterunderstanding of the different macrophages/microglia populationsfunctions, since a controlled immune response is pivotal forpreventing the spread of damage following CNS insult. Recently,Shechter et al. (2009) have demonstrated that, following SpinalCord Injury, resident microglia and infiltrating monocyte-derivedmacrophages differ in their distribution and activities. In particu-lar, they attribute to the last ones a novel anti-inflammatory role inrecovery, which the activated resident microglia is unable toprovide. In addition, the stimulation of reactive T-cell throughvaccination contributes to enhance monocyte recruitment, thusstressing the crucial role of this immune cell type in modulatingCNS immune response.

In the past, results based on neuron-microglia interrelation-ships have preferentially enlightened the side of neuronal damageexacerbation from activated microglia (Spranger and Fontana,1996). However, during the last years, the opposite view hasgained increasing experimental supports and, today, the tradition-al concept that microglia are essentially involved in killing injuredneurons is now recognized as inadequate. Rather, it is becomingclear that a continuous cross-talk, mediated by various signalingmolecules, takes place between neurons and microglia, differentlyregulating these relationships in health and disease. As summa-rized in the upper panel of Fig. 1, the different states of microglialactivation are largely determined by the nature and the extensionof CNS lesion (Lai and Todd, 2008; Ransohoff and Perry, 2009),microglial activation primarily reflecting a physiological mecha-nism aimed at neuroprotection, while overactivation or loss ofmicroglial functions exacerbating a pre-existing neuropathology(Streit and Xue, 2009). Indeed, several authors demonstrated thatmicroglial activation following neuronal injury primarily consti-tutes a brain protective mechanism to limit neurodegeneration, forexample in a model of facial nerve axotomy (Kiefer et al., 1995;Streit et al., 1998). Berezovskaya et al. (1995), in a report based onthe use of op/op mice, which are deficient in the hematopoieticcytokine CSF-1 and present a reduced microglial response,suggested for the first time that microglia activation is aphysiological way to attenuate ischemic damage. In agreementwith these results, there are also growing evidences showing thatmicroglia could be neuroprotective after ischemia (Imai et al.,2007; Kim et al., 2009a,b; Lalancette-Hebert et al., 2007; Neumannet al., 2006; Yanagisawa et al., 2008). Studies aimed to elucidatehow these cells can protect from this insult have demonstratedthat microglia are neurosupportive mainly through cell removal(Napoli and Neumann, 2009) and engulfment of polymorphonu-clear neutrophiles (Neumann et al., 2008), but they are also an

important cellular source for the production of cytokines andneurotrophic factors. (Kiefer et al., 1995; Lambertsen et al., 2009;Madinier et al., 2009) For example, following transient occlusion ofmiddle cerebral artery (Lehrmann et al., 1998) and in thepostischemic hippocampus (Kiefer et al., 1995) in rats, microglialexpression of TGF-beta 1 mRNA does occur, identifying microgliaas the major source of this anti-inflammatory and neuroprotectivecytokines. In addition, post-ischemic proliferation of microgliarepresents an endogenous source of the neuroprotective factorIGF-1 (Lalancette-Hebert et al., 2007). Recently it has also beendemonstrated that microglia protect neurons against ischemiathrough the synthesis of the cytokine tumor necrosis factor (TNF)(Lambertsen et al., 2009). In addition to IGF-I and TNF-alpha, alsoBDNF seems to be an important factor released by microglial cellsand able to modulate the expression of proteins involved in neuralplasticity, such as synaptophysin and GAP-43, following focal brainischemia in rats (Madinier et al., 2009). Interestingly, theproduction of BDNF by activated microglia could also accountfor dopaminergic sprouting into the injured area in an animalmodel of lesioned striatum (Batchelor et al., 1999).

The concept that controlled macrophage/microglia activationcan be beneficial for regenerative processes is well-founded in theperipheral nervous system (PNS) (Aldskogius, 2001; Moller et al.,1996; Prewitt et al., 1997; Rabchevsky and Streit, 1997). In fact, ithas been shown that the poor ability to regenerate of central axons,compared to peripheral axons, correlates with a limited andsuppressed post-injury inflammatory response in the CNS (Schnellet al., 1999). In the PNS, indeed, macrophages/microglia rapidlyinfiltrate lesioned axon bundles and become activated, a processthat correlates with the ability of the PNS to regenerate (Prewittet al., 1997). On the contrary, in the CNS the non-permissiveenvironment and the presence of a brain-resident inhibitoryactivity towards microglia are considered to be primarilyresponsible for the inability of lesioned central axons to regenerate(Hirschberg and Schwartz, 1995; Lazarov-Spiegler et al., 1996,1998; Zeev-Brann et al., 1998). Accordingly, previous exposure ofmacrophages/microglia to PNS nerve tissue, followed by trans-plantation in lesioned CNS districts, was sufficient to stimulatephagocytic activity and to promote some degree of injured centralaxon outgrowth (Lazarov-Spiegler et al., 1996; Rapalino et al.,1998; Schwartz et al., 1999; Zeev-Brann et al., 1998). These resultsstressed the importance of an appropriate ‘‘microglial activation’’to obtain neuroprotection. Accordingly, it has been demonstratedthat activation can be vicariated, at least under some circum-stances, by stimulation of microglia through LPS, a way to ‘‘prime’’macrophages/microglia and to enhance their response to degen-erating central axons (Lazar et al., 1999).

3.2.2. In vitro identification of microglial-secreted neuroprotective

molecules: towards a therapeutic application

The results summarized in the above section clearly point at thepotential role of microglial cells in rescuing injured neurons in in

vivo models of neurodegeneration. The same beneficial activation-dependent neuroprotection has been reported also in in vitro co-cultures studies. For example, microglia-derived production ofneuroprotective factors can protect metabolically impairedneurons (Park et al., 2001) and prevent nitric oxide-inducedapoptosis of cortical neurons in a co-culture model (Toku et al.,1998). Microglial conditioned medium was able to promotesurvival and development of cultured mesencephalic neuronsfrom embryonic rat brain (Nagata et al., 1993) and, in addition,plasminogen (PGn), which was identified as a secretory productfrom microglia, increased dopamine uptake in cultured ratdopaminergic neurons (Nakajima et al., 1994). Another studybased on co-cultures between microglial cells and embryonicdopaminergic neurons revealed that microglia-conditioned

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medium decreased the survival of dopaminergic neurons inprimary cultures and, on the contrary, the direct contact ofmicroglia with the same neuronal cells converted the effect frombeing toxic to becoming survival-promoting (Zietlow et al., 1999).In line with these observations, we have demonstrated thatunstimulated in vitro microglial cells physiologically release in themedium molecule(s) able to rescue neurons in different models ofinduced apoptosis and that, in turn, diffusible signal(s) fromapoptotic neurons enhance microglial neuroprotective properties(Eleuteri et al., 2008; Polazzi et al., 2001). More recently, we haveextended our studies to an in vitro model of 6-hydroxydopamine-induced Parkinson-like neuronal death (Polazzi et al., 2009). Wehave established that microglial neuroprotective action wasexerted through the release of peptidic molecules, which cooper-ate with low molecular weight, heat-resistant factor(s), inneuroprotection. Moreover, we have identified TGF-beta2 as oneof these neuroprotective agents. A neuroprotective effect ofmicroglia mediated by the release of apolipoprotein E (APOE) inthe culture medium was also observed in a model of culture ofneurons exposed to aggregated Abeta 1-40. In this study theimmunodepletion of APOE in microglia APOE isoforms restoredprotection, which, interestingly was potentiated by the presence ofmicroglia-derived cofactors (Qin et al., 2006).

A similar beneficial microglial activation-dependent neuropro-tection has also been reported in another model of in vitro

neurotoxicity, i.e. hippocampal organotypic cultures, wheremicroglia protect against oxygen glucose deprivation (OGD)-induced neuronal damage and engage in close physical cell–cellcontact with neurons in the damaged slice area (Bahr, 1995;Neumann et al., 2006). Moreover, in a co-culture system of BV-2microglia transfected to overexpress the macrophage colony-stimulating factor receptor (M-CSFR) and hippocampal organo-typic slices treated with NMDA, the over-activation of microglialM-CSFR, by endogenous neuronal M-CSF was responsible formicroglial neuroprotection against excitotoxycity, further under-lying the importance of neuronal-microglia dialogue (Mitrasinovicet al., 2005). The impossibility to re-create interrelationshipsbetween neurons and microglia in in vitro systems is an obviouslimitation of studies based on interactions in co-cultures (for acritical review see Carson et al., 2008; Ransohoff and Perry, 2009).However, the knowledge of the basic neuroprotective mechanismsof microglial cells, emerging from these studies, may help inidentifying and targeting specific microglial-produced moleculesthat could account for neuronal survival. Although in vitro systemsprovide a critical tool for exploring many aspects of microglia,removal of these cells from the brain release them from the controlof cerebral microenvironment that determines their phenotypes,neuroprotective versus neurotoxic. For this reason, in in vitro

systems it is important to take into consideration the controlexerted by damaged neurons on microglial neuroprotectivefunctions, as a crucial step in the mechanisms of cerebralinflammation modulation. Concerning this important issue, ithas been demonstrated that severity of neuronal injury is a keyfactor in determining a switch of microglial release from ‘‘toxic’’versus ‘‘protective’’ effectors and, therefore, from neurotoxicityversus neuroprotection (Lai and Todd, 2008). According to thistheory of neuronal control of microglial neuroprotective functions,Figueiredo et al. (2008) have demonstrated, in microglial cells andcerebellar granule neurons co-cultures, the up-regulation ofneuronal FGF-2 expression mediated microglial neuroprotectionagainst excitotoxicity. Another interesting crucial factor releasedby stressed neurons and able to modulate microglial functions isSema3A (Majed et al., 2006). Microglial cells are also regulated byglutamate, since it has been demonstrated that they expressmetabotropic glutamate receptors and that the activation of groupIII mGlu receptors shifted them towards a more neurotrophic

phenotype (Pocock and Kettenmann, 2007; Taylor et al., 2003).Recently, Liang et al. (2010) have demonstrated that glutamateinduced microglial release of neurotrophic factors, such as BDNF,GDNF and NGF, and that the same glutamate released by activatedmicroglia is involved in this mechanism, indicating that glutamatemay serve as a self-limiting system for microglial neurotoxicity.Additional evidences demonstrated that microglial phagocytosis ofapoptotic inflammatory T-cells brought to a decreased productionof pro-inflammatory cytokines, such as TNF-alpha, interleukin-12(IL-12), but it did not affect the secretion of anti-inflammatory andpotentially neuroprotective molecules, such as IL-10 and TGF-beta1 (Magnus et al., 2001). In addition, the microglial interactionwith apoptotic cells induced microglial release of immunoregula-tory and neuroprotective agents, such as prostaglandin E(2), TGF-beta and NGF (Minghetti et al., 2005). These data strongly suggestthat microglial cells not only minimize the dangerous conse-quences of neuronal damage through the elimination of apoptoticcells, but also that the same phagocytic process, as well as theexposure to signal molecules released by dying neurons, promotemicroglial neuroprotection to support the remaining neurons.With all the limitations of the co-culture in vitro systems, thesemodels allow to find microglial-secreted neuroprotective mole-cules and, in turn, to discover neuronal or astrocytic molecules ableto modulates their production. This may provide a noveltherapeutic target for the treatment of neurological disorders, asdiscussed in the next section.

4. Gene delivery of neuroprotective factors to the CNS throughmicroglia: towards a therapeutic approach for NDDs

4.1. Gene delivery of neuroprotective factors to the CNS: basic remarks

Gene therapy and cell grafting, either singularly or incombination, are promising therapeutic approaches for neurode-generative diseases (NDDs) (reviewed by Barkats et al., 1998; Dasset al., 2006; Isacson and Kordower, 2008; Lunn et al., 2009). Sincethe discovery that most NDDs have a genetic component, it has beesuggested that gene therapy could be a potential treatment forthem. Cell transplantation, both for cellular replacement and asvectors for gene delivery, has been proposed for many NDDs, suchas HD, PD, AD and ALS (Aebischer et al., 1996; Backlund et al., 1985;Isacson et al., 1986; Lindvall, 1994; Martınez-Serrano andBjorklund, 1996, 1998; Olson et al., 1994). Most of these studiesmade use of the over-expression of molecules, which are known toplay an anti-apoptotic or pro-survival role, such as neurotrophins,including NGF, BDNF, GDNF or CNTF, or growth factors, as IGF-1,even if in several cases this approach does not completely revertthe pathological features of the diseases (Aebischer et al., 1996;Bjorklund and Kirik, 2009; Cunningham et al., 1994; De Yebeneset al., 2003; Dodge et al., 2008; Emerich et al., 1997; Eslamboliet al., 2005; Frim et al., 1994; Kaspar et al., 2003; Li et al., 2008; Limet al., 2010; Lindvall, 1994; Lo Bianco et al., 2004; Martınez-Serrano and Bjorklund, 1996, 1998; McBride and Kordower, 2002;McBride et al., 2006; Olson et al., 1994; Popovic et al., 2005;Ramaswamy et al., 2009; Wang et al., 2002). The identification ofnew neuroprotective factors, in particular the discovery of pro-survival and/or anti-apoptotic substances physiologically releasedby non-nervous cells of the brain, assumes a fundamental role withregards to the purpose of new therapeutic applications of genetransfer in NDDs.

4.2. Identification of new neuroprotective factors: from in vitro

studies to a therapeutic approach

As it has been previously described in Section 3.2.2, microgliaproduce and release many neuroprotective factors, mainly

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proteins (Polazzi et al., 2001). Among these factors, we haveidentified TGF beta-2 (Polazzi et al., 2009), and other groups havefound additional factors (Liang et al., 2010; Magnus et al., 2001;Minghetti et al., 2005; Qin et al., 2006), but most of them are likelystill to be discovered. The identification of these neuroprotectivemolecules released by microglia in physiological conditions couldbe the starting point for a new therapeutic approach for NDDs, asshown in Fig. 2. In particular, moving from the observations thatmicroglia, either in unstimulated conditions or exposed to toxicstimuli (Polazzi et al., 2001, 2009), produce and release severalpotentially neuroprotective factors, the dissection of the ‘‘secre-toma’’ of microglia is central to find new molecules to be furthertested for their neuroprotective potential. In this framework, the

[(Fig._2)TD$FIG]

Fig. 2. Gene delivery of neuroprotective factors to the CNS through microglia. In the upp

NDDs. According to this picture, microglia in physiological condition is in an ‘‘alerted state

antioxidants and growth factors. Following a toxic stimulus, genetic or environmental, l

thus continuing to produce the same factors, but being also able to perform clearance of

prolonged toxic stimulus, microglia become ‘‘pathologically-activated’’. In this state, m

inflammatory cytokines, ROS and NO. The identification of the many neuroprotective fac

vivo or ex vivo approaches for microglial-mediated gene delivery, either directly or ind

shown in the right lower panel and described in Section 4.3.

proteomic approach seems to be particularly adequate to identifythe microglial secreted-molecules in different physiopathologicalconditions and it further underlines the importance of in vivo

systems for preliminary studies in the neurodegeneration/neuro-protection field (Glanzer et al., 2007; Liu et al., 2008; Reynoldset al., 2009; Zhou et al., 2005). Identification of microglial-releasedneuroprotective factors could bring to deliver, either in microgliaor in BM-derived cells, the identified neuroprotective microglialcells genes for proteins that will be then expressed, processed andeventually released by the infected cells, through specific viralvectors. The flexibility of viral vector system, concerning the use ofdifferent vectors with specific natural tropisms towards thedifferent cell types, of different serotypes (at least for AAV) and

er panel, it is illustrated a comprehensive view of microglial phenotypic changes in

’’, characterized by the release of many factors, such as anti-inflammatory cytokines,

imited as intensity and/or duration, these cells become ‘‘physiologically-activated’’,

aggregates and phagocytosis of cell death debries. As a consequence of a strong or

icroglia persists in clearance and phagocytosis, but they also start to release pro-

tors released by microglia, indicated in the left lower panel, will bring to develop in

irectly through BMT, of potentially neuroprotective factors to the CNS in NDDs, as

E. Polazzi, B. Monti / Progress in Neurobiology 92 (2010) 293–315306

of different promoters, specifically designed for a cell-specific geneexpression, makes it possible to develop the optimal targetingapproach (Colin et al., 2009; Shevtsova et al., 2005). Therefore,these viral vectors could drive expression of various microglial-derived neuroprotective genes into sick brains, thus reinforcing thephysiological microglial neuroprotective phenotype, which getslost in pathological conditions in most of NDDs, as stated by the‘‘microglial-dysfunction hypothesis’’ (Banati and Graeber, 1994;Farfara et al., 2008; Gebicke-Haerter et al., 1996; Simard andRivest, 2007; Streit, 2004). This phenotype is mainly mediated bythe release of a broad panel of factors, such as cytokines,antioxidants, neurotrophins and lysosomal enzymes, as describedin Sections 3.2.1 and 3.2.2 (Fiala et al., 2007; Garden and Moller,2006; Glanzer et al., 2007; Glezer et al., 2007; Polazzi et al., 2009;Polazzi et al., 2001; Polazzi and Contestabile, 2002; Turrin andRivest, 2006; Vila et al., 2001). A possible pitfall of this kind ofapproach is the possibility that gene delivery through viral vectorinfection or microglial grafting or both in a pathological conditioncould stimulate microglial over-activation and, consequently, giverise to inflammation. However, it has been demonstrated that it ispossible to perform these therapies associated with a pharmaco-logical treatment able to control inflammation, as described inSections 2.3.1 and 2.3.2, without affecting the efficiency of thetransplantation system (Malm et al., 2008). Thus, in principle, anovel experimental strategy with potentially high therapeuticimpact for NDDs may be developed.

4.3. Microglia as a target and a vehicle for CNS gene therapy

The combination of gene transfer techniques and transplanta-tion of glial cells is a promising approach to deliver therapeuticmolecules into the CNS. The first attempt to use gene therapytowards glial cells came from studies on a metabolic neurologicaldisease, the Lesch-Nyhan syndrome (Gruber et al., 1985). Later on,it was shown that astrocytes genetically modified to over-expressneurotrophins or L-DOPA promoted survival and correct function-ing of neuronal grafts in rat models of neurodegeneration,especially PD (Cunningham et al., 1994; Lundberg et al., 1996;Smith et al., 1996). Recently, it has been proposed the use ofastrocytes for motor neuron diseases, such as ALS, emphasizingtheir potential as therapeutic targets and agents in cell replace-ment therapy. In particular, a reduction in astrocytic expression ofmutant SOD1 slows disease progression and has a positive effecton life span (Blackburn et al., 2009). The use of adult astrocytes ascellular vehicles for ex vivo gene transfer represents a particularlywell-suited system, because of their CNS origin, their efficientsecretory mechanisms and their role of neuronal support (Ridetet al., 1999). Moreover, this approach implies an autologoustransplantation, thus obviating immunological rejection and theside effects of immune-suppressors (Arnhold et al., 2002). Inaddition to astrocytes, also microglia are now considered a goodcell vehicle for brain gene transfer, for the same reasons above-mentioned regarding astrocytes. In particular, bone marrowtransplantation (BMT) can be used to introduce geneticallymodified brain macrophages and microglia (BMM) into adultbrain to express recombinant therapeutic proteins (Asheuer et al.,2004; Guo et al., 2004). In fact, the transplantation of either normalor genetically modified cells, into which the normal gene has beenpreviously inserted in vitro, from allogeneic or autologous BM, hasbeen proposed not only for the treatment of genetic diseases,whose clinical expression is restricted to lymphoid or hematopoi-etic cells, but also for generalized genetic diseases, especially thoseaffecting CNS (Parkman, 1986). BMT from wild-type (WT) miceprolongs life span and ameliorates neurologic manifestations inmodels of metabolic neurological diseases (Jin et al., 2002; Leimiget al., 2002; Norflus et al., 1998). As previously described in Section

1.2, BM cells migrate into the brain and differentiate into microglia,when exposed to a neuronal environment (Eglitis and Mezey,1997; Ladeby et al., 2005; Theele and Streit, 1993; Vitry et al.,2003), thus underlying the possibility of using BMT for NDDstreatment (Azizi et al., 1998; Bahat-Stroomza et al., 2009; Dezawaet al., 2004; Kopen et al., 1999; Mezey et al., 2000, 2003; Sykovaand Jendelova, 2007; Tondreau et al., 2008). In particular, theymigrate in the brain preferentially towards injured areas (Ladebyet al., 2005; Poon et al., 2006; Sadan et al., 2008; Sykova andJendelova, 2007). In fact, the improvement due to BMT does notdepend on the replacement of the lost neurons, but most probablyon glial increased expression levels of different factors, such asneurotrophins and pro-survival cytokines (Blandini et al., 2010;Garcıa et al., 2004; Pisati et al., 2007), as well as on theirimmunomodulatory and phagocytic effects (Kang and Rivest,2007; Karussis et al., 2008; Kim et al., 2009b; Ohtaki et al., 2008;Simard et al., 2006). For example, it has been shown that in ALSmice WT BMT derived-microglia, as well as astrocytes, could delaydegeneration and extend survival of mutant SOD1-expressingmotoneurons (Appel et al., 2008; Beers et al., 2006; Clement et al.,2003; Corti et al., 2004; Ohnishi et al., 2009; Vercelli et al., 2008).Moreover, in AD mice, BMT from WT mice reduces Abetadeposition and rescues memory deficits through a restoration ofdefective microglial function, as Abeta degradation and decreasedinflammation (Lee et al., 2010b).

More interestingly, the demonstration of an injury-enhancedrecruitment of BM-derived cells into lesioned hippocampus, raisesthe possibility of using genetically manipulated BMT cells asvectors for lesion-site-specific gene therapy even in minimallyinjured areas of the CNS (Biffi et al., 2004; Ladeby et al., 2005). Inparticular, BM cells have been ex vivo genetically modified andreimplanted in a transgenic mouse model of a neurodegenerativedisorder, metachromatic leukodystrophy (MLD). These cells andtheir progeny delivered therapeutic genes to the CNS, through anextensive repopulation of genetically modified CNS microglia, thusreconstituting the enzyme activity and preventing the develop-ment of neuropathological abnormalities typical of the disease(Biffi et al., 2004). In general, genetically manipulated BM derivedcells are able to correct the enzyme defect of the CNS in lysosomalstorage diseases in neurons, as well as in glial cells and in cellsassociated with blood vessels, both in animal models and inpatients (Cartier et al., 2009; Hahn et al., 1998; Lake et al., 1995;Lonnqvist et al., 2001; Tsuji et al., 2005; Walkley et al., 1994). BMcells can transduce viral vector expression of L-DOPA, in both in

vitro and in vivo models of PD (Schwarz et al., 1999, 2001).Moreover, transplantation of neurotrophin-gene-modified BMcells into animal models of AD, PD and MS showed that thesecells survived, migrated into brain and expressed the neurotro-phins, leading to neuroprotection and symptomatic improvement(Li et al., 2008; Makar et al., 2009; Sadan et al., 2009).

5. Conclusions

The idea of a protective autoimmunity of the brain has beendeveloped in the last few years and has brought to deviseimmunomodulatory therapies for neurodegenerative diseases,thus augmenting the protective and regenerative aspects of theimmune system for neuroprotection in brain diseases (Angelovet al., 2003; Bakalash et al., 2005; Butovsky et al., 2006a,b; Graberand Dhib-Jalbut, 2009; Schwartz and Kipnis, 2004). In addition, inthe same period, several data have been published supporting theconcept that microglia exert a neuroprotective effect and induceneurogenesis, mainly through the release of soluble factors(Polazzi and Contestabile, 2002; Whitney et al., 2009). These dataled to change the traditional view of microglia in neurodegenera-tive diseases: from the idea that these cells play an harmful role for

E. Polazzi, B. Monti / Progress in Neurobiology 92 (2010) 293–315 307

neuronal degeneration due to a gain of their inflammatoryfunction, to the new proposal of a loss of microglial neuroprotec-tive function as a causing factor in neuropathologies. In vitro

models appear to be more and more important to clarify the basicmechanisms of microglial-mediated neuroprotection, in order toidentify microglial-secreted neuroprotective factors. Notwith-standing the intrinsic limitation of these in vitro models, theyare essential for the identification of potentially effectiveneuroprotective molecules (Polazzi and Contestabile, 2002;Polazzi et al., 2001, 2009), to be further tested in in vitro and in

vivo models of neurodegenerative diseases. In addition, microglialcells are emerging as a promising target to design new therapeuticapproaches in a gene therapy set-up for neurodegenerativediseases, acting as both a target and a vehicle for gene deliveryof neuroprotective factors to the CNS (Asheuer et al., 2004; Guoet al., 2004). In particular, even in a pathological situation,microglial cells could be driven to over-express neuroprotectivemolecules, endogenously produced by them in physiologicalconditions, thus strengthening the intrinsic microglial neuropro-tective phenotype. This strategy is based on a relatively simpleconcept, considered rather unconventional until 10–15 years ago,but that is presently well-established, that in neurodegenerativepathologies neurons can be protected from death and recover fromdamage favoring the acquisition of a ‘‘more neuroprotective’’phenotype by microglial cells (Polazzi and Contestabile, 2002),together with the novel technological approaches of viral vectordelivering of genes for therapeutic purposes and of grafting ofgenetically modified cells. It is only with a thorough understandingof these fields that novel, safe and efficient gene therapy strategiescan become clinically applicable treatments. It has also becomeclear that there will probably be a need for multiple alternativetherapeutic strategies, including gene therapy, cell grafting andpharmacological treatments and acting via different mechanisms,to provide optimal treatment to each neurodegenerative diseasespatient who might be suffering from different causes or severity ofdisease.

Acknowledgements

The present work was supported by a young investigator grantof the University of Bologna for strategic research to B.M. Theauthors are grateful to A. Contestabile for critically reading themanuscript.

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