Funciones inmunomoduladoras de la galectina-3 en condiciones de neurodegeneración

Recent findings suggest an important role of neuroinflammation in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, which are debilitating, expensive and largely untreatable conditions strongly linked with age. Microglia are the innate immune cells of the brain that, under homeostatic conditions, constantly survey their environment and prune neuronal synapses. Following an insult or injury, these cells become activated and can perform a wide array of functions by production of pro-inflammatory and neurotoxic factors, as well as protective, anti-inflammatory and phagocytic functions. In chronic neuroinflammatory states seen in neurodegenerative diseases a unique disease-associated phenotype is observed. Selective mutations in microglia/myeloid-specific genes, including the glycoprotein triggering receptor on myeloid cells 2 (TREM2), have been associated with Alzheimer’s disease. Recent evidences have suggested TREM2 to be instrumental in neuroinflammation and linked to microglia neurodegenerative/disease-associated phenotype. One protein which induces this phenotype is galectin-3, which binds complex glycans in glycoproteins. Galectin-3 is expressed and released specifically by highly activated microglia in the injured brain and can propagate inflammation by binding glycoproteins such as TLR4, and also TREM2. In this presentation I will address whether galectin-3 also contributes to detrimental neuroinflammation in Alzheimer’s pathology, and, hence, could be a therapeutic target.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microglial subtypes: diversity within the microglial community

Microglia are brain-resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single-cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or "subtype") displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.España, Ministerio de Ciencia, Innovación y Universidades FEDER y UE RTI2018-098645-B-10

Dieta de los grandes fitófagos silvestres del Parque Nacional de Doñana - España

Se estudia la alimentación del jabalí, gamo y ciervo en el Parque Nacional de Doñana desde 1979 a 1981 empleándose simultáneamente 3 métodos que permitieron registrar 1 156 observaciones; 193 contenidos estomacales examinados y 360 análisis de excrementos. Se muestran también datos sobre la preferencia de los fitófagos para explotar los recursos en 6 biotopos considerados. En todos los casos se dan resultados de la frecuencia de presencia y peso de los componentes ingeridos. El jabalí se alimenta con frecuencia en la marisma consumiendo rizomas de castañuela (scirpus maritimus). El gamo explota más los recursos del pastizal o borde de marisma siendo la grama (cynodon dactylon) el componente más consumido. Y el ciervo aprovecha el monte blanco más que las otras especies consumiendo jaguarzo (halimiun halimifolium). La comparación de las dietas da como resultados una aparente solapación del gamo tanto con el jabalí como con el ciervo por lo que podemos inferir que el jabalí y el ciervo habían definido sus nichos tróficos en Doñana antes de la introducción del gamo.España. Instituto de Cooperación IberoamericanaTesi

Effective Knockdown of Gene Expression in Primary Microglia With siRNA and Magnetic Nanoparticles Without Cell Death or Inflammation.

Microglia, the resident immune cells of the brain, have multiple functions in physiological and pathological conditions, including Alzheimer's disease (AD). The use of primary microglial cell cultures has proved to be a valuable tool to study microglial biology under various conditions. However, more advanced transfection methodologies for primary cultured microglia are still needed, as current methodologies provide low transfection efficiency and induce cell death and/or inflammatory activation of the microglia. Here, we describe an easy, and effective method based on the Glial-Mag method (OZ Biosciences) using magnetic nanoparticles and a magnet to successfully transfect primary microglia cells with different small interfering RNAs (siRNAs). This method does not require specialist facilities or specific training and does not induce cell toxicity or inflammatory activation. We demonstrate that this protocol successfully decreases the expression of two key genes associated with AD, the triggering receptor expressed in myeloid cells 2 (TREM2) and CD33, in primary microglia cell cultures

Mitochondrial toxins and neurodegenerative diseases

The selective loss of a particular subset of neurons is a common feature of neurodegenerative disorders. A failure in respiratory chain complex activities in mitochondria seems to be a causative factor. The aim of this review is to describe the most important toxins affecting the mitochondrial function, which could be involved in the incidence of some of these diseases: MPTP, rotenone and 3-nitropropionic (3-NPA)

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 μg of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-α; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.España,Ministerio de Educación y Ciencia Grants SAF2002-01952 and SAF2004-0660

Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease

The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson’s disease. Brain inflammation, microglia and astroglia activation, disruption of the blood–brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson’s disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia.España MINECO y FEDER SAF2015-64171-