GliaNews Bulletin Vol.l Year 2016 / www.glianews.org/

Glia as a pharmacologic target The study of glia will revolutionise the current knowledge within the

field of neuroscience and excellent works have been showing the potential use of glial cells as therapeutic targets. However, glia physiology is still an unknown field despite of the long time in

researching and several efforts.

Perspective ln Glia: Are Alzheimer's etiology a

pericyte-fungal interaction?

lnterviews Drª . Penha Cristina Barradas: Glia and

the effects of thyroid hormone on oi igodendrocyte development.

Are a Metabolism / lnflammation /

Transmission / Cancer / Behavior / Cognition

GliaNews Ι

Pag. 4: Editorial / GliaNews Bulletin Release Vol. 1 Year 2016.

Pag. 5: Editorial considerations / Considerations about gliaas a pharmacologic target.

Pag. 6: Interview / Glia and the effects of thyroid hormone on oligodendrocyte development.

Pag. 8: Metabolism / Leptin action on astrocytes: possible news mechanisms for food control.

Pag. 9: Inflammation / How to get multiple sclerosis? Several gaps, many questions and hypotheses often contradictory make difficult the finding of a cure.

Pag. 10: Transmission / Astrocytes not only link distant synapses, it may also be a link between different symptoms present in different diseases.

Pag. 11: Cancer / Perspective and advances in astrocytomas research: how nitroproteinas may indicative a new field.

Pag. 12: Behavior / Can microglia modulate sexual behaviour?

Pag. 14: Perspective In Glia / Are Alzheimer's etiology the fungis/pericytes interation?

About the site:

Science advances approving or rejecting hypotheses born in therestless minds. However all creativity springs from a priorknowledge. When the scientific world thinks knows everything the realityshows that little was advanced. However, define what is theforefront of knowledge is also uncertain and only the time can toevaluate if the body of knowledge that was discussed and testedresulted in significant advancement for the science. The GliaNews proposes publicize, encourage and promotediscussions about the hidden side of the CNS: the glial cells. Theglia cells are very plastic, are involved in several cognitivefunctions higher and we believe that the increase in research onglial cells will provide vital information for better understanding ofthe brain, with significant advances for a better future.

You find on the site:

- Weekly columns of students in the area of glia.

- Publications showing the importance of progress in research onglial cells in different areas of study

- Comments on revisions that show future fields of study.

- Our Perspective In Glia, where we comment on a work inneuroscience, which makes no reference to glia, and suggest wherethey can bring an advance for that model, situation or case study.

- Interviews with researchers regarding advances and perspectivesin research on glial cells

- Interview with doctoral students on their projects

- News published by graduate programs and dissemination portalsin neuroscience.

- News talking about the projects of researchers who work withglial cells.

GliaNews Ι

Ι Content

General editor

Michael Luiz Martins Rocha

Rio de Janeiro State University (UERJ)

Review and translation

Mellanie Dutra

Rio Grande do Sul Federal University (UFRGS)

Teodoro Manso

SESC School Garden - Mato Grosso do Sul (MS)

Art and Images

Denyse Ane

Rio de Janeiro State University (UERJ)

Diagramation

Andre Nascimento

Rio de Janeiro State University (UERJ)

Ι Team

GliaNews Ι Considerações editoriais published online 21 January 2016

By Michael Luiz

GliaNews Bulletin Release Vol. 1 Year 2016.

In order to emphasise even more the importance of glia in the field of neuroscience, we arereleasing our newsletter, published every 3 months.

he study of glia will revolutionise the current knowledge within the field of neuroscience. However, due to the great amount ofworks published in each knowledge area, the time of the majority of the researchers to know more about other areas becomesshorter day by day. This way, every 3 months, we will gather in a newsletter, the topics of PEG, of the areas and the interviews

published on the website so that you who already follows the website can spread, forward, share and/or disseminate a succinct material thatmakes the reader gain time acquiring a great amount of knowledge in a few minutes.

TWe wish everyone an excellent reading.

Published 28 January 2016

Ι Editorial

GliaNews Editorial considerations Ι www.glianews.org published online 28 January 2016

GliaNews Ι Considerações editoriais published online 21 January 2016

By Michael Luiz

Considerations about glia as a pharmacologic target.

n March of 2015, GliaNews was officially launched inBrazil, aiming to popularized and disseminate the researcheswith glia cells, and in December of the same year, after an

acquisition period of considerable experience in the outreach work,we release the English version aiming to spread the work performedfor an international setting.

IThroughout this period, we report several works in which the

increase of knowledge about the physiology and the function of gliacells in the nervous system drives to new pharmacologic targets,what is natural in the research, once the patients are in a hurry.Nevertheless, it is noteworthy our attention and care with importantconsiderations concerning the research about glia.

First of all, despite of the long time in researching and severalefforts, glia physiology is still an unknown field, even more thanneuron’s. For instance, we do not have yet full knowledge of thefunction in a healthy brain of some kinds of for example microglia,such as NG2 cells or oligodendrocytes of the grey substance.Besides, we do not know yet which is the extension ofheterogeneity in each glial kind and how that can impact thefunction of the cell. Mentioning astrocytes, the best characterisedand studied kind, we know that this has a range of morphologicaldistinctions concerning the localization within the parenchyma andthe brain region, resulting in functional distinctions and in theexpression of proteins as aquaporins, glutamate conveyors,connexins among others for instance, and in these context, apharmacological modulator for the reception of glutamate inastrocytes in the cortical parenchyma could have a different impacton the perivascular astrocytes function in the maintenance of theblood-brain barrier. However, excellent works have been showingthe path to be followed in the potential use of astrocytes astherapeutic targets, such as can be seen in the review of Anna MariaColangelo et alii “Astrologliosis as therapeutic target forneurodegenerative diseases” of the year 2014.

On the other hand, a great range of works show a strongrelationship of neuroinflammation with several psychiatricdisturbances and disorders, with the consequent connection of themicroglial functions to such morbidities, some even suggesting thechanging of the microglial function as schizophrenia etiology, ascan be observed in Juan C. Leza et alii “Inflammation inschizophrenia: A question of balance” and of Réus GZ et alii “Therole of inflammation and microglial activation in thepathophysiology of psychiatric disorders”. In this last point, recentevidences show that antipsychotics used in clinic such aschlorpromazine, haloperidol, clozapine and olanzapine affect deeplymicroglial physiology, and have a considerable anti-inflammatoryeffect. Here it is important to highlight that microglia is a cell thatmay present various states, varying from the resting to thephagocyte form, from anti to anti-inflammatory profile. Not onlythat, microglial functions also seem to vary considerably regardingthe sex and, even the length of the blue wave used in optogeneticsmay modulate microglia, causing the adoption of an anti-

inflammatory profile, showing how delicate is the regulation of thiscellular kind, and how little we still know.

In this context, it is a task of extreme responsibility to knowwhich will be the long-term in vivo response of a pharmacologicalmodulator about glial function for example. Could it be possiblethat trying to cure a disorder, we could provoke a deeper change inthe physiology of these cells, culminating in the emergence ofanother disorder with a greater impact on the quality of life?

Thus, along with our role of disseminating and informing aboutthe glial researches, we also highlight the importance of the cautionthat new drugs must have about the modulation of these so complexcells. If simple neuronal monoamine receptors may already cause arange of side effects, what to say of future and potential glialmodulators. Notwithstanding, the serious, responsible and carefulwork will certainly bring to pharmacology the necessary andexpected advance to neuroscience.

Published 21 January 2016

Astrogliosis as a therapeutic target for neurodegenerative diseases. ColangeloAM et al. Neurosci Lett. 2014 Apr 17;565:59-64.

Inflammation in schizophrenia: A question of balance. Leza JC et al. NeurosciBiobehav Rev. 2015 Aug;55:612-26.

Role for microglia in sex differences after ischemic stroke: importance of M2.Bodhankar S et al. Metab Brain Dis. 2015 Dec;30(6):1515-29.

The role of inflammation and microglial activation in the pathophysiology ofpsychiatric disorders. Réus GZ et al. Neuroscience. 2015 May 14.

Ι Editorial considerations

GliaNews Editorial considerations Ι www.glianews.org published online 21 January 2016

Glia and the effects of thyroid hormone onoligodendrocyte development.In the last years, glial research have grown in Brazil and among several projects, Penha Cristina, PhD,investigates the cellular mechanism of myelination in the CNS.

Pricipais linhas de pesquisa:

- Brain injury in perinatal hypoxia and mobilization ofneural precursor cells by thyroid hormone; - Effects of protein malnutrition in a restricted phase ofCNS development, on the regulation of the centralaction; - Effects of thyroid hormone deficiency on differentiationof oligodendrocytes and myelination.

GN: Do you think that more glial researchescame a little late comparing to the scientificadvancement in the international scenario oris it following the current technologicaladvances?

PC: Certainly. The glia is known a long timeago, from the identification of neurons.However, technical limitations may explainsome of this delay. I believe it is theconsequence of the natural evolution ofknowledge. With the identification of newtechniques, neurotransmitters, cell signalingpathways, the involvement of trophic factorsthat may act both in neurons and in glial cells,it is natural that it took a longer time, sinceneurons have always been "main actors”. Inthis way perhaps this is why the knowledge ofglial cells has come a little later, but it's agrowing movement over time.

For example, at congresses like the AmericanSociety of Neurosciences there are alreadyspecific symposia on glia. W observe thatgrowth. Now we have specific event, specific

societies of glial cells, networks of Americanand European studies. As it’s discover thatthese cells have much to contribute, glialresearch will evolving and growing. In 1989,Glia journal was launched, giving a highlightpoint. Even today it serves as one of thereferences for professionals in the area as agood vehicle for the study of glia cells. Whilenot the only source, it was a great turningpoint.

GN: Your work focuses on the effect ofthyroid hormone in the differentiation andmaturation of oligodendrocytes. How wouldthis action occur in glial cells, and how it cancause harm to a newborn in adult life?

PC: The question of the effect of thyroidhormone, the nervous system has been knowna long time. There is an important clinicalcondition that is hypothyroidism and it hasdifferent effects if installed in adult life or indevelopment. During pregnancy if hormonelevels are reduced, this will cause importanteffects on the development of the fetal centralnervous system. When levels are severelyreduced, that condition can generate cretinism(congenital hypothyroidism), with specificdamage on the general development, mentalretardation, reducing the formation of neurons,connections among them and other damage.

These researches are already known a longtime and a high number of them have alreadybeen published in the 60s and 70s. In the 80s,researches focusing on oligodendrocytes havebegun. The first studies reported much aboutthe effect of thyroid hormone on theproliferation and differentiation of these cells.Signals in progenitor cells to proliferate or notproliferate are different accordint to whichreceptor is activated. That's because we knowthat a molecule can have different effects in acell depending on the receptor in which it willact.

This is the case of thyroid hormone inoligodendrocytes. Depending on thedifferentiation phase, oligodendrocytes canhave different receptor types, and because ofit, we may see different effects. In the 90s toearly 2000, it has become more complex the

understanding about the process ofmyelination. That's when our group beganworking with late effects of the thyroidhormone in the differentiation ofoligodendrocytes in the aspect of myelinationitself (in trigger the formation andmaintenance of the myelin sheath). We are stillfocusing in this area once the process ofmyelination is not fully known. There is still alot to understand the training process, whichregulates the beginning, which defines howmany lamellae (turns) the myelin sheath willgive. Currently, we work with the modulationof signaling pathways, induced by thyroidhormones to understand how these cells willinteract with the fibers and initiate thesignaling process.

When the process does not occur adequatelythe main consequences are: in the absence ofthyroid hormones during development, thenumber of myelinated fibers is lower, bringingconsequences for nerve impulse conduction(less myelin sheath, the speed will be slower).Then the consequences will be functional,motors, deafness due to auditory perceptionchanges, visual and mental retardation.

GN: One of their research projects involvesthe hypoxia-ischemia model. Many studiesrecently are linking various diseases of theCNS, directly or indirectly, with themicroglia. Could microglia in the hypoxia-ischemia model be involved and interact witholigodendrocytes?

PC: Certainly, the microglia is a peculiar cell.Starting at the source, which was a point ofdebate for a long time, there is still doubtabout them. It is known that the source ofmicroglia is not the same as the other glialcells. They are called macrophages of the CNSand is believed that at some point indevelopment, cells of the mesenchymallineage (monocytes) invade the CNS, beingplaced there through the life, and when there isany damage, or a situation outsidehomeostasis, they are activated. One type ofthis activation is processed as an inflammatoryresponse and today it is known that these cellsproduce molecules both pro- inflammatoryand anti-inflammatory.

INTERVIEWS

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In this aspect, microglia can be good guys orbad guys, all tending to homeostasis. When westarted to look more deeply at AIDS forexample, it emerged many works relating theaction of microglia to this disease, withimmunosuppression. There is a big discussionabout it. Now we are discussing about theinitial defense against viral agents which maybe present even in neurodegenerative diseases.There is an investigation being conducted inthis scenario, not only in ischemic hypoxiamodel, but in other injury models in the CNSrelated to an important interaction. In thiscase, they may be interacting witholigodendrocytes, demyelinating diseases andalso diseases of the immune system.

There are also studies that say that microgliacan stimulate the production of myelin, whileothers say it could lead to death, which is nowrong, what changes is what releasedmolecule is modulating these situations.

GN: Another issue is, in Brazil, there areseveral groups working glia, the number ofresearchers increased, what is yourperspective on the growth of glial cell studiesin Brazil?

PC: Certainly Brazil follows what is alreadybeing done in international context, often nothaving the speed that we would like to performscience. When I started working with research,almost only one group (where I worked) wasworking with glia. And it was more or less inthe boom of the glial cell studies. And we seemore and more, if you follow the programs ofinternational congresses. At 1984, when Ipresent the first work for Congress, our workhad many interesting results in the study ofglial cells. This happened for a long time butnow we see it widespread in Brazil, we seeimportant groups working with glial cells.

I think that's great, because it increases the

study of glia. In addition, it is what we see inthe world. Then, picking up a book ofabstracts of Science, Neuronscience, in 80s,there were very few researchesbut in a discreetproportion and the idea that glia was just thereto help and work with the neuron. Today wesee that there are the glia-glia interactions. Thefunctioning of glial cells is important not onlyfor neurons, but also for other glial cells. It hasno effect on cell itself (autocrine effect), but itcan release factors that modulate its functionand modulate other glial cells in differentphases.

to the fact that injuries have an effect in thedevelopment stage does not mean that it willbe the same in another. The life expectancy ofthe population is increasing, and also thephysiology changes. The brain cells of an agedperson is different than a new person. We alsoknow we do no produce new neurons, as skin,for example. This is a highly regulated andmodulated phenomenon as it should be..

About this research

Penha is a medical and associate professor at the Rio de Janeiro State University (UERJ). She is reviewer of important scientific journals such thePLoS Journal and the Journal of Neuroscience Research. She coordinates research projects with oligodendrocytes at the Laboratório de Neurobiologiaof UERJ. She was one of the first researchers to work in Brazil with glial cells, integrating one of the pionnering groups in this study, the researchgroup of Professor Leny Cavalcante in Universidade Federal do Rio de Janeiro (UFRJ). In addition, the first article in the Glia Journal published bybrazilian group has been hers in 1989, entitled "Astroglial differentiation in the opossum superior colliculus".

GliaNews Interview Ι www.glianews.org published online 04 November 2015

Leptin action on astrocytes: possible new mechanisms forfood control.Know we everything regarding leptin?

ecently, at 2014, Kim JG et al, of Yale UniversitySchool of Medicine confirmed evidence thatleptin also acted on the hypothalamic astrocytes.

The group noted the functional presence of the long form ofthe leptin receptor in this glial type. Particular part of theastrocytic functions, astrocytes are known to regulate a largenumber of synapses through their interaction with processessynapses (astrocytic domain), and in the rodent brain a singleastrocyte could cover hundreds of thousands of synapses.

R

Not only by releasing gliotransmissores (moleculesreleased by astrocytes with similar action toneurotransmitters), some studies show that the synapticdensity in a region may increased or decreased due to"physical" coverage of astrocytic processes in neurons. Forexample, a larger coverage area in neuronal soma byastrocytic processes physically prevents the occurrence ofaxo-somatic synapses. In study by Kim et al, the conditionaldeletion of receptor leptin only in the astrocytes, causedalteration of astroglial morphology and consequently in theinput synaptic in hypothalamic neurons related to the feedingcontrol, besidess changes in the food comportamen afterpresence of leptin. They also verified that after fasting orghrelin administration, these modified animals had anexaggerated increase in food intake. All results show therelevance of leptin action on the hypothalamic astrocytes tofood intake.

In August this year (2015), Wang Y et al, in a study published in JMol Neurosci, corroborated the findings of Kim, adding otherperspectives. The focus was the deletion for all forms of leptinreceptor, again only in astrocytes, and what would be theconsequence of the exposure of these animals to a fat diet for twomonths. Without dietary manipulation, these animals had attenuatedpSTAT3 signaling in the arcuate nucleus of the hypothalamus 30minutes after intracerebroventricular delivery of leptin and afterhyperlipidc diet, these had the increase of fat mass percentage, sericleptin levels and obesyti.

The importance of astrocytes in food modulation is alsomentioned in other studies. I remember an article by astrocytic NPYexpression, and after this, I search for NPY expression inastrogliosis present in my undernutrition model, without success,perhaps because of ultradian fluctuations. Away from the NPYastrocytic, same studies are linking ontogenetic plasticity withincreasing reactive gliosis, as seen in working Younes-Rapozo Vwhere rat pups were exposed to nicotine after 2 postnatal day, anddevelop features of the metabolic syndrome in adulthood. Ofcourse, rats have a peak leptin about P10, serving for the growthprojections of the ARC towards the other hypothalamic nuclei, onetrophic role by leptin during early posnatal development, unlike tofood regulation in adulthood.

No work is reported that leptin may have a special feature on theastrocyte development at early posnatal development, and if this

could affect the ontogenetic plasticity. Many new fields are open tonew works that wish to observe the presence or absence of NPYvesicles NPY inside astrocytes on other nutritional models, and newpossible functions by leptin in the astrocytic population during thedevelopment.

Published 04 December 2015

Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding.Kim JG et al. Nat Neurosci. 2014 Jul;17(7):908-10.

Role of Astrocytes in Leptin Signaling. Wang Y et al. J Mol Neurosci. 2015Aug;56(4):829-39.

Neonatal nicotine exposure leads to hypothalamic gliosis in adult overweight rats.Younes-Rapozo V et al. J Neuroendocrinol. 2015 Oct 10.

Ι Ι MetabolismMetabolism

GliaNews Area Metabolism Ι www.glianews.org published online 04 December 2015

How to get multiple sclerosis? Several gaps, many questionsand hypotheses often contradictory make difficult thefinding of a cure.Better understanding between the oligodendrocytes and microglia interaction is a way to beadvanced.

ultiple sclerosis (MS) is a disease in which themyelin sheath, which is formed byoligodendrocytes processes involving the

axons of the neurons, are damaged by inflammatoryprocesses. As myelin is responsible for the increase in thespeed of propagation of the nerve impulse, oncecompromised, the axons can not transmitting the actionpotential of a neuron to the other, causing a wide spectrum ofsigns and symptoms that frequently results in the loss ofphysical capabilities and / or cognitive.

M

Although the etiology of MS is unknown, several geneticand environmental factors have been proposed as potentialfacilitators of the development and progression of MS,including viral infections, specifically by Epstein-Barr virusand also by the human herpes virus type 6 since antibodiesand antigens related to these pathologies have been detectedin the brains and cerebrospinal fluid of patients with MS.However, the ratio of viral infection with MS is not yet veryclear, and some groups suggest that it could somehow limitdisease progression. It is the view of Savarin C et al.,published in the Journal of Neuroinflamation in Novemberthis year (2015), in which they highlight a correlationbetween decreased incidence of infectious diseases in recentdecades with increased incidence of autoimmune diseases,including MS.

In MS, T-cells attack the myelin after being stimulated cellspresenting antigen, and although it is described that this situationcan be enhanced by prolonged viral infections such as in chronicinfection in the CNS triggered by TMEV virus (Theiler's murineencephalomyelitis virus ), where is observed growing tissuedestruction accompanied by an ascending paralysis (resembling thesymptoms of MS infection in experimental models withdemyelination triggered by activation of the immune system in thepresence of JHMV (neurotropic mouse hepatitis virus (MHV) strainJHM), the persistence of infection is correlated with clinicalrecovery.

Another point on the multiple sclerosis refers to the mechanismas the lesions in myelin are initiated. Recently two differentneuropathological findings have been reported, both characterizedby the absence of T cell infiltration and demyelination eventsindicating prior lesions observed in MS. The first concerns the"microglial nodules" (NMGs) where the damaged axons wereassociated with a small number of macrophages/microgliaaggregates in the white matter still normal. In these situations,microglia expressed MHC II, while the positive axons had notphosphorylated neurofilaments and Y1 receptor, suggesting thatthese axons were undergoing degeneration. The second findingsuggested an antecedent condition neuropathological characteristics

of MS lesions called "newly formed lesion (LRF)", which iscomposed of oligodendrocyte apoptosis, and microglial activationwith little or no lymphocyte infiltration.

Despite these two conditions are being identified as differentconditions, Sato F et al suggest that both descriptions correspond tothe same event, but with different techniques, since they werefocused on different aspects of the pathogenesis of MS (one focusedon other axons and oligodendrocytes), mentioning that in fact canbe complementary. For example, in demyelination the authors reportthat were observed both "NMGs" as "LRFs" in the central nervoussystem. Understanding the early events of injury in MS, theinteraction between microglia and oligodendrocytes, and how viralinfections can influence this interaction may yield promising targetsfor development of new therapeutic strategies in the fight againstMS.

Published 10 December 2015

"Microglial nodules" and "newly forming lesions" may be a Janus face of early MSlesions; implications from virus-induced demyelination, the Inside-Out model. Sato Fet al. BMC Neurol. 2015 Oct 24;15:219.

Self-reactive CD4(+) T cells activated during viral-induced demyelination do notprevent clinical recovery. Savarin C et al. J Neuroinflammation. 2015 Nov11;12(1):207.

Ι Ι InflammationInflammation

GliaNews Area Inflammation Ι www.glianews.org published online 10 December 2015

Astrocytes not only link distant synapses, it may also be alink between different symptoms present in differentdiseases.Astrocytes promise to revolutionize our understanding of the neuronal pathways due toparticipation in the endocannabinoid system and the purinergic signaling.

strocytes have several functions in the nervoussystem and one of these is the the ability tomodulate the activity of synapses, which may

result in changes in behavior and memory. Astrocytesrespond to neuronal activity increasing intracellular CA2+levels and this increase leads to exocytosis of vesiclescontaining VAMP2, VAMP3, vSNARE, which are storedgliotransmissores such as (glutamate, d-serine, ATP /adenosine, for example), and these gliotransmitters arerelease into the synaptic cleft (see the full list on reviewselected last week).

A

For a long time, it was known that astrocytes express theendocannabinoid receptor-1 (CB1R), but the function wasnot well understood. Actually, it is being revealed thatastrocytes promote a bridge between the endocannabinoidand glutamatergic signaling (pathways inhibitory andexcitatory respectively). After the retrograde release ofendocannabinoids in the synaptic cleft, these molecules bindto the astrocytic CB1R, increasing intracellular Ca2+ levelsthat are propagated to astrocytes neighbors via gap junctionscausing at farthest astrocytes the release of glutamate,stimulating neighboring synapses (approximately 60μm).

After administration of endocannabinoids in a singlesynapse there is a set of activation and inhibition patterns inthe synaptic activity in the brain, showing how is complexthe signaling in the nervous system, and some studies show thatablation of astrocytic CB1R lead to behavioral and memorychanges. These processes are examples of the action of astrocyticlateral modulation in the nervous system, and increase theimportance of the tripartite synapses as a neuronal modulator.

In addition, several studies relate symptom overlap in disordersand neurological diseases that affect the memory such as thetemporal lobe epilepsy (TLE), Alzheimer's disease (AD),Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS)could be related to synaptic, sinaptotoxidade dysfunction, andastrocytic function.

Boisson D & Aronica E report the involvement of adenosinereleased by astrocytes in TLE, AD, PD, ALS, by adenosine kinase(ADK) overexpression, reporting this alteration as a commonpathological brand of these comorbidities. In the same article, theyargue that in a "comorbidity model transgenic", in which the ADKoverexpression in the brain result in deficiency of adenosine, isobserved a comorbidity spectrum seizures, changes in dopaminergicfunction, attention, sleep regulation and cognitive deficits,suggesting that adenosine signaling dysfunction is common inneurological conditions and can dysfunction of this gliotransmitterexplain theses phenotypes of co-morbidity.

These mechanisms of gliotransmission related here

(endocannabinoid signaling and ATP/adenosine release) openresearch areas for the discovery of modulators of astroglial functionto improve the memory in several disorders and neurologicaldiseases.

Published 18 December 2016

Expression and cellular function of vSNARE proteins in brain astrocytes. Ropert Net al. Neuroscience. 2015 Oct 27.

Comorbidities in Neurology: Is adenosine the common link? Boison D & Aronica E.Neuropharmacology. 2015 Oct;97:18-34.

Ι Ι TransmissionTransmission

GliaNews Area Transmission Ι www.glianews.org published online 18 December 2015

Perspectives and advances in astrocytomas research: hownitroproteinas may indicate a new field.Gene mutations confer susceptibility to cancer development, but changes in protein residues mayalso be one of the pillars of the problem.

dvances in characterization of biomarkers ingliomas this leading to a review of theclassification of this type of cancer which

originates from glial cells (learn more) and increasing theknowledge of the peculiarities in different subtypes willallow the development of pharmacological strategies evermore effective.

AIn vivo, the increase in nitric oxide (NO) and superoxide

(O2-), in pathological situations lead to the formation ofperoxynitrite anion, which is highly reactive and can interactwith tyrosine residues of proteins, leading to nitration, animportant posttranslational modification event. Thesemodifications may in turn compromise the electric charge ofresidues located in a region in the protein that interacts withanother protein or a specific substrate (in the case ofenzymes for example), thus compromising the function ofthe protein.

In December this year, in a study published by Peng F etal, in the Journal of The American Society for MassSpectrometry, researchers, wanted to observe how was thenitroproteinas profile in astrocytomas. Not only verify, theyalso created a methodology that allows the study and moredetailed characterization of protein - "the method queintegrated 2DGE, Western blot, LC-MS / MS, and literaturedata-based bioinformatics system to discover in vivonitroproteins and Their nitrotyrosine sites, and to rationalize thefunctions of each nitroprotein ".

In this study the research identified with MS/MS analysis a totalof 18 nitroproteins wich are envolved in drug-resistance, signaltransduction, cytoskeleton, transcription and translation, cellproliferation and apoptosis, immune response, phenotypicdedifferentiation, cell migration, and metastasis. Two proteins washighlighted: nitro-sorcin and nitro-β-tubulin. The first is a calciumbinding protein involved in drug resistance and metastasis. Thisprotein might play a role in the spread and treatment of astrocytomaand sorcin expressions were found among different grades ofastrocytomas with an increase of the nitration level in high-gradeastrocytoma relative to control. The second protein β-tubulin is acytoskeletal protein and involved in the cell migration. As nitro-sorcin, β-tubulin showed increased expression among differentgrades of astrocytomas relative to controls and semiquantitativelyincreased nitration level in high-grade astrocytoma relative tocontrol.

The great heterogeneity of gliomas unfortunately results in acomplex scenario that becomes almost impossible to find a generalpharmacological approach. As a result, many researchers haverecently begun to study the tumor microenvironment (TME)seeking a new target for the development of techniques aimed ateliminating, regression or stabilization of the tumor. Thismicroenvironment is mainly composed of nontumor cells,highlighting microglia and macrophages, which are then called,

tumor-associated microglia and tumor-associated macrophagesrespectively. At 2012, Engler and colleagues reported on a subgroupof astrocytomas an increase in gene expression found in tumor-associated microglia.

Microglia have a characteristic which is well known in therelease of nitric oxide (NO) in inflammatory situations. Asmentioned earlier, the microenvironment near the tumor is beingviewed more carefully so as highlighting the microglia.Furthermore, gliomas are widely known for their recurrence aftersurgical removal. One question that remains to be in at leastastrocytomas, a possible release of NO by microglia nextmicroenvironment, after removal of glioma, could lead to changesin protein residues by nitration restarting the tumorigenic process.As the nitric oxide is a soluble factor, is consistent think of himinteracting with intracellular proteins in astrocytes, which could beone of the causes for the recurrence of gliomas, noting that theactual impact of nitration in the development of gliomas is still notfully understood . But these are points only time and science mightsay.

Published 22 December 2015

Nitroproteins in Human Astrocytomas Discovered by Gel Electrophoresis andTandem Mass Spectrometry. Peng F et al. J Am Soc Mass Spectrom. 2015Dec;26(12):2062-76.

Increased microglia/macrophage gene expression in a subset of adult and pediatricastrocytomas. Engler JR et al. PLoS One. 2012;7(8):e43339.

Therapeutic targeting of tumor-associated macrophages and microglia inglioblastoma. Bowman RL and Joyce JA. Immunotherapy. 2014;6(6):663-6.

Ι Ι CancerCancer

GliaNews Area Cancer Ι www.glianews.org published online 22 December 2015

Can microglia modulate sexual behaviour?Recent projects suggest an active participation of microglia about the sexual differentiation, butwhat about in adult life?

icroglia is a kind of cell highly dynamic andthat performs an important role in the neuralinflammation. However, recent projects are

spreading the area of importance of this glial kind.MFor instance, Schwarz and collaborators showed that the

number and the morphology of microglial cells throughoutthe development depend on the individual’s sex and age, aswell as the brain region of interest, at least in rodents.Researchers observed that males have more microglial cellsat the beginning of the postnatal development [4th day],while females have more microglial cells with anamoeboid/active morphology later in the development,between the 30th and the 60th day of postnatal life, withdrastic variations being also observed in gene expression fora great number of cytokines, chemokines and their receptorsin these cells.

Nevertheless in 2013, Lenz and collaborators showed thatmicroglia of preoptic area (POA) are fundamental for themasculinization of rodents. They found that flavouredestradiol from testosterone stimulates the production ofprostaglandin E2 (PGE2) which causes an increase ofdendritic spines in males in the POA, being this increaserelated with the masculinization of the behaviour. At thebeginning of the development, the density of microglial cellswith amoeboid shape is higher than in females, as well asthey present a more active morphologic profile and theadministration of estradiol or PGE2 was able to “masculinize” thenumber and the morphology of microglial cells in females ifadministered just after birth.

Not only that, PGE2 administered to females at the beginning ofthe development made them develop a pattern of sexual behaviourin adult life similar to that observed in males. Notwithstanding,when PGE2 was administered with minocycline, a microglialinhibitor, this change of behavioural pattern did not occur, just asdifferences in the morphology of microglial cells were not observed,nor the increase of the density of dendritic spines produced byPGE2 in POA. Not only important for the differentiation in thesexual maturity, microglial cell activation differs between men andwomen in adult life after insults.

Many psychological disturbances linked to stress such as theposttraumatic stress disorder and depression are related tomicroglial activation and susceptibility to such disorders differsbetween men and women being the dysfunction in the medialprefrontal cortex (mPFC) a key factor in many of these disorders.Bollinger and collaborators showed that nonstressed females have agreater branched microglial density in mPFC than males, and afterthat acute and chronic stress, there is a reduction in the proportionof the branched microglia and in the expression of CD40 in females,without changing the profile of activation in males’ microglia.

Besides, Bodhankar and collaborators’ study in vitro alsosuggests that there is a considerable difference between males’ andfemales’ microglia concerning the response and interaction of these

cells with B cells after a brain damage. Thus, may sexual libido andattraction behaviours in adult life be linked to the response ofmicroglia after sexual hormone variations? These are certainlyscenes of a next episode related to microglial function.

Published 19 January 2016

Microglia are essential to masculinization of brain and behavior. Lenz KM et al. JNeurosci. 2013 Feb 13;33(7):2761-72.

Sex differences in microglial colonization of the developing rat brain. Schwarz JM etal. J Neurochem. 2012 Mar;120(6):948-63.

Differential effects of stress on microglial cell activation in male and female medialprefrontal cortex. Bollinger JL et al. Brain Behav Immun. 2015 Oct 9.

Role for microglia in sex differences after ischemic stroke: importance of M2.Bodhankar S et al. Metab Brain Dis. 2015 Dec;30(6):1515-29.

Ι Ι BehaviorBehavior

GliaNews Area Behavior Ι www.glianews.org published online 19 January 2016

Cortical astrocytes contribute to motor learning: thehypothesis of astrocytes in the modulation of motorbehavior.Very involved with the coordination of motor activities, the Bergmann glia in the cerebellum has avery important assistance in this role, at least within the cortex, and possibly in other regions of thebrain.

ognition consists of learn new skills, and thus,when we started walking, cycling, a new series ofexercise while we are acquiring new knowledge,

visual changes occur in the nervous system, in an importantbrain region involved in motor function: cerebellum. In thisregion, there is a type of specialized radial glia, the gliaBergmam, which modulates the activity of neurons andcerebellar inhibitory interneurons.

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However, similar to other higher cognitive functions,which involve the participation of more than one brainregion, recent studies are finding that astrocytes present inthe cortex and striatum also play a key role in the modulationof motor function. It is well known that after the release ofneurotransmitters, these molecules are able to bind toreceptors present in astrocytes, leading to increase inintracellular calcium by opening calcium channels present inastrocyte membrane, or by the release of calcium present inthe reticulum rough endoplasmic through activation IP3R2astrocytic receptors. Consequently, the increase inintracellular calcium within the astrocytes leads to release ofgliotransmissores such as D-serine, molecules that modulatesynaptic activity.

In a study by Padma Shri and colleagues, the groupstudied the role of astrocytes in motor learning. Theyobserved that in mice where the astrocytes had increasedintracellular calcium decreased by reducing signaling IP3R2presented motor learning deficits, as well as in the motor cortex LTPwas blocked. However, in these same animals, D-serine wassufficient to reverse the effects and group concluded that Ca2 +signaling in the astrocytes is of utmost importance during thedriving motor skills for the purpose that learning occurs normally.

The importance of this field of study can bring light with respectto mechanisms involved in the loss of coordination and movementsobserved in neurodegenerative diseases such as Huntington'sdisease (HD), a genetic disease which leads to neurodegeneration instriatum cortex and hippocampus, and causes deficiencies in motoractivity. Chakraborty et al, Using an animal model that mimics HDsymptoms by brain injury caused by the administration of 3-nitropropionic acid (3- NP), an irreversible inhibitor ofmitochondrial complex II, found that quercetin, a type of flavonoid,attenuated significant deficits in motor coordination and motioninduced by 3-NP as well as decreased microglial proliferation andincrease in the number of astrocytes in the nucleus of the lesion.

In this study, the researchers did not give emphasis on action ofquercetin on the function of astrocytes, however some studies havediscussed the possible neuroprotective effect of flavonoids on thistype glial. As mentioned, recent studies have shown the importance

of astrocytes in the modulation motor learning, and we pointed outhere would not be possible if the motor improvements of mice inthe study of Chakraborty et al could be in part due to the increase ofastrocytes. But these are scenes of a next chapter.

Published 26 January 2016

Motor-Skill Learning Is Dependent on Astrocytic Activity. Padmashri R et al. NeuralPlast. 2015;2015:938023.

Quercetin improves behavioral deficiencies, restores astrocytes and microglia, andreduces serotonin metabolism in 3-nitropropionic acidinduced rat model ofHuntington's Disease. Chakraborty J et al. CNS Neurosci Ther. 2014 Jan;20(1):10-9.

Ι Ι CognitionCognition

GliaNews Area Cognition Ι www.glianews.org published online 26 January 2016

Are Alzheimer's etiology a pericyte-fungal interaction?Several studies show that the blood-brain barrier failures are related neurodegenerative diseases.However, these faults can be the beginning of everything?

THE STUDY

n the year of 1906 the German psychiatrist andneuropathologist Alois Alzheimer observed aworrisome clinical situation. This was the patient

Auguste Deter, who at age 51 had progressive memory loss,combined with the disorientation and language disorders.After the onset of symptoms, a patient unfortunately died at55, and postmortem analysis of Auguste's brain by Dr.Alzheimer relevaram the first morphological changes in thebrain associated with the disease later named afterAlzheimer's disease (AD ).

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Currently, AD is the most common form of dementia andis usually diagnosed after age 65, and despite the associationwith age, there are cases in which it arises early. Althoughthere is no cure for AD and also not be known diseaseetiology, scientific research over the years have broughtconsiderable knowledge regarding importantneurophysiological changes related to onset of symptoms,and / or during the course of the disease.

The main changes widely described in the literature is theformation of senile plaque by accumulation of beta amyloidprotein and the neurofibrillary tangles resulting inhyperphosphorylation of tau protein, in addition to neuronalloss and reactive gliosis, and although not a definitive proofthat the "trigger" that triggers all these changes, many researchersargue that the DA may have a microbial etiology. It seems strange,but several studies support this view, and a few time, was publishedin Scientific Reports, the work of Diana Pisa and collaborators,coordinated by Professor Luis Carrasco, where the authors showthat the central nervous system tissue of patients with AD fungalcells present, and hyphae, unlike the brain of patients controls keptin the same conditions.

The researchers observed that neuronal cells also showed fungalDNA inside your body cell, and the presence of such results wereobserved in different brain regions, as external frontal cortex,cerebellar hemisphere, entorhinal cortex, hippocampus and choroidplexus. A fungal infection was also observed by the group in bloodvessels, which the authors say, could also explain the vascularpathology often detected in patients with AD. In the study group,the researchers found evidence of infection from Candida albicansand Saccharomyces cerevisiae, even by Neosartorya hiratsukae, andall results article can be seen with the use of imunifluorescênciatechniques the presence of fungal material (DNA, proteins) bothinside and outside neurons.

THE PERSPECTIVE

The blood-brain-barrier (BBB) is a tightly regulated interface inthe central nervous system (CNS), which controls the exchange ofmolecules in brain blood, thus ensuring the homeostasis of the CNS.Not only that, she is also an important defense against infection andbrain against the body's own immune cells attack. The BBB iscomposed of the neurovascular unit (NVU), which is formed byendothelial cells (ECS), the pericytes and the astrocytes. Astrocytesare essential for the formation and maintenance of the BBB tosecrete factors that lead to proper association between the cells andthe BBB formation of "gap junctions". Several studies have shownthat disruption in Alzheimer disease exist in the BBB, involving lossof the permeability barrier and phenotypic changes in NVU cells.

In other studies, it is shown that the BBB dysfunction triggers a

range of neurotoxic effects like oxidative stress, neuroinflammation,the alteration of the permeability, in addition to dysregulation ofnitric oxide, a key regulator of regional blood flow. Like that, BBBdysfunction to also mediate a vicious circle, in which cerebralperfusion is further reduced and the neurodegenerative process isaccelerated, and in this context, the interaction of endothelial cellswith pericytes and astrocytes could also play a significant role in theprocess, perhaps even the main one.

Ι Ι Perspective In GliaPerspective In Glia

Regarding the pericytes, studies show that the cells suffer

degeneration in AD. Being a single position within theneurovascular unit between the endothelial cells of brain capillaries,astrocytes and neurons, pericytes regulate very importantneurovascular functions such as certification, the formation andmaintenance of vascular stability and angioarchitecture, in additionto the flow regulation capillary blood and clearance of toxicproducts generated by the cells.

Linking to pericytes these cells have a specific receptor foramyloid beta protein subsequently degrading such proteins withinthe pericytes. This receptor is the LRP-1 and in vitro, prolongedexposure of these cells to beta amyloid protein leads to cell death,possibly explaining the pericytes reduction observed in AD patients.However, other studies showed that can also result in loss ofpericytes in the absence of beta-amyloid protein, leading toneurodegeneration events similar to those observed in AD, raisingthe question whether the degeneration of pericytes by prologadaexposure to beta amyloid protein could not be a secondary effectwhich would worsen loss already pre-existing

In the images of Pisa article, where various fungi are also presentin the blood vessels, there is no way not to think that these samefungi could initially infect the brain pericytes, providing a break inthe barrier blood-brain, leading to a subsequent infiltration fungi inthe brain parenchyma. In response, the protein beta-amyloid, whichcould be produced in an attempt to contain the infection, sincestudies have shown it has an anti-fungicidal action, in this secondstage, the increased protein beta amyloid could lead to more deathUNV pericytes, leading to an increase in the failure BBB, allowingentering more fungi.

Looking through this scenario, even possible to speculate that theneurodegeneration observed in AD could be an action of the body'sown killing infected cells, since fungal DNA was found insideneurons in the study of Pisa. Thus, it is our PEG: fungi, perhapsparticularly Candida albicans initially, could be infecting pericytes,leading to breakdown in the BBB and this is the aetiology of AD:fungal infection in glial cells? However, that only time and sciencecan answer. Finally, strongly recomento reading from Pisa andemployees work and the work of Winkler and collaborators, in theyear 2014, where they postulate the involvement of percitos withAlzheimer's disease, highlighting are those cells, forgotten elementswhen speaks disease.

Published 28 November 2015

Different Brain Regions are Infected with Fungi in Alzheimer's Disease. Pisa D et al.Sci Rep. 2015 Oct 15;5:15015.

Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review ofendothelium-mediated mechanisms and ensuing vicious circles. Di Marco LY et al.Neurobiol Dis. 2015 Aug 23. pii: S0969-9961(15)30034-6.

Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease.Cabezas R et al. Front Cell Neurosci. 2014 Aug 4;8:211.

The pericyte: a forgotten cell type with important implications for Alzheimer'sdisease? Winkler EA et al. Brain Pathol. 2014 Jul;24(4):371-86.

About author Michael Luiz were graduated in biology from the UERJ (emphasison biomedicine), and currently investigate in an undernoutritionmodel the effects of ontogenetic plasticity in neurogêneses andgliogênese. He is editorial director and founder of the GliaNews.

GliaNews Area Metabolism Ι www.glianews.org published online 28 November 2015