Immune Response In Brain Research Articles

Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration.

Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.

Association Analysis of Peripheral and CSF Biomarkers in Late Mild Cognitive Impairment.

Research shows that late mild cognitive impairment (LMCI) has a high risk of turning into Alzheimer’s disease (AD). Due to the invasion of detection methods and physical damage to the patients, it is not a convenient way to diagnose and detect early AD and LMCI by cerebrospinal fluid (CSF) data. So there is an urgent need to find the correlation between peripheral biological data and CSF data in the brain, and to find new diagnostic methods through changes in the peripheral biological data. Studies have shown that during the pathogenesis of LMCI and AD, peripheral immune cells specifically infiltrate into the brain through the blood–brain barrier, causing an imbalance in the brain’s immune response and dysregulating the clearance of Aβ in CSF. Therefore, in this paper, canonical correlation analysis (CCA) algorithm is presented to derive the correlation between peripheral and CSF biomarkers based on LMCI peripheral gene expression data and plasma marker information. Firstly, to explore the influence of the infiltration of peripheral blood immune cells on the brain, the abundance of 28 immune cells were calculated by using the gene set enrichment analysis algorithm of LMCI samples. Then, to identify the correlation between biomarkers inside and outside of the brain, we performed CCA to calculate the relationship between CSF and peripheral biomarkers. Results of CCA showed significant correlations between the variable sets of 8 peripheral biomarkers and the variable sets of CSF biomarkers (at 0.794). Finally, according to Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis, it was found that the obtained peripheral biomarkers are involved in many immune-related pathways and functions which can be activated in peripheral blood of LMCI patients. Most related genes enriched in immune-related pathways and functions were up-regulated. Through receiver operating characteristic curve (ROC) analysis, it was also found that FP40/FP42 and type 1 T helper can accurately predict the pathological changes of LMCI (at 0.747).

Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension.

Mounting evidence indicates that the renin-angiotensin (RAS) and immune systems interact with one another in the central nervous system (CNS) and that they are importantly involved in the pathogenesis of hypertension. Components comprising the classic RAS were first identified in the periphery, and subsequently, similar factors were found to be generated de novo in many different organs including the brain. There is humoral-neural coupling between the systemic and brain RASs, which is important for controlling sympathetic tone and the release of endocrine factors that collectively determine blood pressure (BP). Similar to the interactions between the systemic and brain RASs is the communication between the peripheral and brain immune systems. Systemic inflammation activates the brain’s immune response. Importantly, the RAS and inflammatory factors act synergistically in brain regions involved in the regulation of BP. This review presents evidence of how such interactions between the brain RAS and central immune mechanisms contribute to the pathogenesis of hypertension. Emphasis focuses on the role of these interactions to induce neuroplastic changes in a central neural network resulting in hypertensive response sensitization (HTRS). Neuroplasticity and HTRS can be induced by challenges (stressors) presented earlier in life such as a low-dose of angiotensin II or high fat diet (HFD) feeding in adults. Similarly, the offspring of mothers with gestational hypertension or of mothers ingesting a HFD during pregnancy are reprogrammed and manifest HTRS when exposed to new stressors as adults. Consideration of the actions and interactions of the brain RAS and inflammatory mediators in the context of the induction and expression of HTRS will provide insights into the etiology of high BP that may lead to new strategies for the prevention and treatment of hypertension.

Parkinsonian neurotoxicants impair the anti-inflammatory response induced by IL4 in glial cells: involvement of the CD200-CD200R1 ligand-receptor pair

Exposure to pesticides such as rotenone is a risk factor for Parkinson’s disease. Dopaminergic neurons are especially sensitive to the toxicity of compounds that inhibit the mitochondrial respiratory chain such as rotenone and 1-methyl-4-phenylpyridinium (MPP+). However, there is scarce information on their effects on glia. To evaluate whether these neurotoxicants affect the immune response of glia, primary mouse mixed glial and microglial cultures were treated with interleukin (IL) 4 in the absence and presence of MPP+ or rotenone. Using qRTPCR or western blot, we determined the expression of anti-inflammatory markers, the CD200R1 microglial receptor and its ligand CD200, and genes regulating glycolysis and oxidative metabolism. ATP and lactate levels were additionally determined as an index of cell metabolism. Microglial phagocytosis was also evaluated. MPP+ and rotenone clearly abrogated the IL4-induced expression of anti-inflammatory markers in mixed glial cultures. CD200 and CD200R1 expression and microglia phagocytosis were also affected by the neurotoxicants. Changes in the mRNA expression of the molecules regulating glycolysis and oxidative metabolism, as well as in ATP levels and lactate release suggested that metabolic reprogramming in response to MPP+ and rotenone differs between microglial and mixed glial cultures. These findings support the hypothesis that parkinsonian neurotoxicants may impair brain immune response altering glial cell metabolism.

Bat mammalian orthoreoviruses cause severe pneumonia in mice

Mammalian orthoreovirus (MRV) infections are ubiquitous in mammals. Increasing evidence suggests that some MRVs can cause severe respiratory disease and encephalitis in humans and other animals. Previously, we isolated six bat MRV strains. However, the pathogenicity of these bat viruses remains unclear. In this study, we investigated the host range and pathogenicity of 3 bat MRV strains (WIV2, 3 and 7) which represent three serotypes. Our results showed that all of them can infect cell lines from different mammalian species and displayed different replication efficiency. The BALB/c mice infected by bat MRVs showed clinical symptoms with systematic infection especially in lung and intestines. Obvious tissue damage were found in all infected lungs. One of the strains, WIV7, showed higher replication efficiency in vitro and vivo and more severe pathogenesis in mice. Our results provide new evidence showing potential pathogenicity of bat MRVs in animals and probable risk in humans.

Fentanyl self-administration impacts brain immune responses in male Sprague-Dawley rats

Opioid use disorder (OUD) affects over two million in the United States and is an increasing public health crisis. The abuse of fentanyl and the emergence of potent fentanyl derivatives increases the risk for the user to succumb to overdose, but also to develop OUD. While intense attention is currently focused on understanding the complexity of behaviors and neural functions that contribute to OUD, much remains to be discovered concerning the interactions of opioid intake with the immune response in the central nervous system (CNS). In the present studies, we tested the hypothesis that short-term abstinence from fentanyl self-administration associates with altered expression of innate immune markers. Male Sprague-Dawley rats were trained to self-administer fentanyl (0.0032 mg/kg/infusion) to stability followed by 24 h of abstinence. Several innate immune markers, as well as opioid receptors (ORs) and intracellular pattern recognition receptors (PRRs), were interrogated within nodes of the neurocircuitry involved in OUD processes, including the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIP) and midbrain (MB). In the present study, few immune targets were impacted in the PFC and MB during short-term abstinence from fentanyl (relative to saline) self-administration. However, increased expression of cytokines [e.g., interleukin (IL)1β, IL5], chemokines [e.g., C–C motif chemokine 20 (MIP3α)], tumor necrosis factor α (TNFα) and interferon (IFN) proteins (e.g., IFNβ and IFNγ)] was seen in the NAc, while decreased expression of cytokines (e.g., several ILs), chemokines [e.g., granulocyte–macrophage colony-stimulating factor (GMCSF), monocyte chemoattractant protein (MCP) MCP1, MIP3α], the chemokine ligand 5 (RANTES) and interferons (e.g., IFNβ and IFNγ) in the HIP. Positive correlations were observed between cumulative fentanyl intake and expression of IL1β and IL6 in the NAc, and significant negative correlations with fentanyl intake and IFN β, IL2, IL5, IL12p70 and IL17 in the HIP. Few changes in OR expression was observed during early abstinence from fentanyl self-administration. Excitingly, the expression of the PRR, stimulator of interferon genes (STING) negatively correlated with cumulative fentanyl intake and significantly correlated to specific cytokines, chemokines and interferon proteins in the HIP. Although the CPu appears relatively invulnerable to changes in innate immune markers, the highest correlations between cumulative fentanyl intake with MAVS and/or STING was measured in the CPu. Our findings provide the first evidence of CNS innate immune responses and implicate STING as novel mechanistic targets of immunomodulation during short-term abstinence from fentanyl self-administration.

Impaired Innate Immunity Mechanisms in the Brain of Alzheimer's Disease.

Among environmental factors likely associated with Alzheimer’s disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain. In particular, mRNA levels of IRF7, MED23, IL28B, and IFN-α genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE ε, IRF7, MED23, and IL28B gene polymorphisms. Most AD patients showed decreased mRNA levels of all investigated genes in the hippocampus and temporal cortex. However, a small group of AD patients showed increased hippocampal mRNA expression of MED23, IL28B, and IFN-α. mRNA levels of MED23, IL28B, IFN-α from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE ε4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-α. These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, might affect brain immune efficiency.

Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior.

BackgroundMaternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programing of the fetal brain is a lesser-explored area. The goal of this study was to investigate the impact of two chowmaternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal and adult behavior in a mouse model.MethodsThroughout pregnancy and lactation, female C57Bl/6J mice were fed one of two standard, commercially available chow diets (pellet versus powder). The powdered chow diet was relatively deficient in micronutrients and enriched for carbohydrates and n-3 long-chain polyunsaturated fatty acids compared to the pelleted chow. RNA was extracted from embryonic day 15.5 forebrains and hybridized to whole genome expression microarrays (N = 5/maternal diet group). Functional analyses of significantly differentially expressed fetal brain genes were performed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. Neonatal behavior was assessed using a validated scale (N = 62 pellet-exposed and 31 powder-exposed). Hippocampal learning, locomotor behavior, and motor coordination were assessed in a subset of adults using fear conditioning, open field testing, and Rotarod tests (N = 16 pellet-exposed, 14 powder-exposed).ResultsComparing powdered to pelleted chow diets, neither maternal weight trajectory in pregnancy nor embryo size differed. Maternal powdered chow diet was associated with 1647 differentially expressed fetal brain genes. Functional analyses identified significant upregulation of canonical pathways and upstream regulators involved in cell cycle regulation, synaptic plasticity, and sensory nervous system development in the fetal brain, and significant downregulation of pathways related to cell and embryo death. Pathways related to DNA damage response, brain immune response, amino acid and fatty acid transport, and dopaminergic signaling were significantly dysregulated. Powdered chow-exposed neonates were significantly longer but not heavier than pelleted chow-exposed counterparts. On neonatal behavioral testing, powdered chow-exposed neonates achieved coordination- and strength-related milestones significantly earlier, but sensory maturation reflexes significantly later. On adult behavioral testing, powdered chow-exposed offspring exhibited hyperactivity and hippocampal learning deficits.ConclusionIn wild-type offspring, two diets that differed primarily with respect to micronutrient composition had significant effects on the fetal brain transcriptome, neonatal and adult behavior. These effects did not appear to be mediated by alterations in gross maternal nutritional status nor fetal/neonatal weight. Maternal dietary content is an important variable to consider for investigators evaluating fetal brain development and offspring behavior.

ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer's disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

Risperidone Ameliorates Prefrontal Cortex Neural Atrophy and Oxidative/Nitrosative Stress in Brain and Peripheral Blood of Rats with Neonatal Ventral Hippocampus Lesion.

Reduction of the dendritic arbor length and the lack of dendritic spines in the pyramidal cells of the prefrontal cortex (PFC) are prevalent pathological features in schizophrenia (SZ). Neonatal ventral hippocampus lesion (NVHL) in male rats reproduces these neuronal characteristics and here we describe how this is a consequence of BDNF/TrkB pathway disruption. Moreover, COX-2 proinflammatory state, as well as Nrf-2 antioxidant impairment, triggers oxidative/nitrosative stress, which also contributes to dendritic spine impairments in the PFC. Interestingly, oxidative/nitrosative stress was also detected in the periphery of NVHL animals. Furthermore, risperidone treatment had a neurotrophic effect on the PFC and antioxidant effects on the brain and periphery of NVHL animals; these cellular effects were related to behavioral improvement. Our data highlight the link between brain development and immune response, as well as several other factors to understand mechanisms related to the pathophysiology of SZ.SIGNIFICANCE STATEMENT Prefrontal cortex dysfunction in schizophrenia can be a consequence of morphological abnormalities and oxidative/nitrosative stress, among others. Here, we detailed how impaired plasticity-related pathways and oxidative/nitrosative stress are part of the dendritic spine pathology and their modulation by atypical antipsychotic risperidone treatment in rats with neonatal ventral hippocampus lesion. Moreover, we found that animals with neonatal ventral hippocampus lesion had oxidative/nitrosative stress in the brain as well as in the peripheral blood, an important issue for the translational approaches of this model. Then, risperidone restored plasticity and reduced oxidative/nitrosative stress of prefrontal cortex pyramidal cells, and ultimately improved the behavior of lesioned animals. Moreover, risperidone had differential effects than the brain on peripheral blood oxidative/nitrosative stress.

CNS myeloid cell heterogeneity at the single-cell level

Abstract The cellular composition of the central nervous system (CNS) is highly complex and dynamic. Regulation of this complexity is increasingly recognized to be spatially and temporally dependent during development, homeostasis and disease. Context-dependent cellular heterogeneity was shown for neuroectodermal cells as well as the myeloid compartment of the CNS. The brain myeloid compartment comprises microglia and other CNS-associated macrophages. These are brain-resident cells with critical roles in brain development, maintenance, and immune responses during states of disease. Profiling of CNS myeloid cell heterogeneity has been greatly facilitated in the past years by development of high-throughput technologies for single-cell analysis. This review summarizes current insights into heterogeneity of the CNS myeloid cell population determined by single-cell RNA sequencing and mass cytometry. The results offer invaluable insights into CNS biology and will facilitate the development of therapies for neurodegenerative and neuroinflammatory pathologies.

Constrained sialic acid donors enable selective synthesis of α-glycosides.

Sialic acid is a sugar residue present in many biologically significant glycans of mammals, commonly as a terminal α-glycoside. The chemical structure of sialic acid, which features an anomeric center with carboxyl and methylene substituents, poses a challenge for synthesis of the α-glycoside, thus impeding biological and therapeutic studies on sialic acid-containing glycans. We present a robust method for the selective α-glycosidation of sialic acid using macrobicyclized sialic acid donors as synthetic equivalents of structurally constrained oxocarbenium ions to impart stereoselectivity. We demonstrate the power of our method by showcasing broad substrate scope and applicability in the preparation of diverse sialic acid-containing architectures.

Sweet spot for making oligosaccharides

Sugar Chemistry Sugars pose a challenge for chemists: how to string together functional group–rich building blocks that can adopt multiple conformations. Two papers in this issue used sugar building blocks constrained by a macrocyclic linker to encourage formation of a specific glycosidic linkage (see the Perspective by Pohl). Ikuta et al. used glucose building blocks containing a linker that changes the sugar conformation to synthesize cyclic oligomers with only three or four units. The linker changes the conformation of the glucose monomers, enabling them to come together despite the strain in the final structure. Komura et al. prepared sialic acid building blocks with a linker that allows for selective formation of the α-anomeric linkage with a range of nucleophiles. They synthesized dimers of sialic acid with many different linkages and a pentamer with four α(2,8) linkages. This method enabled chemical synthesis of components of mammalian glycans involved in brain development, cell adhesion, and immune response. Science , this issue p. [674][1], p. [677][2]; see also p. [631][3] [1]: /lookup/doi/10.1126/science.aaw3053 [2]: /lookup/doi/10.1126/science.aaw4866 [3]: /lookup/doi/10.1126/science.aax3501

Conformationally supple glucose monomers enable synthesis of the smallest cyclodextrins.

Cyclodextrins (CDs) are cyclic oligomers of α-1,4-d-glucopyranoside and are known mainly as hexamers to octamers. The central cavities of CDs can retain small molecules, enabling diverse applications. The smallest members, CD3 and CD4, have ring sizes too small to permit the most stable conformations of glucopyranose and have not been accessible synthetically. In this study, we present methods to chemically synthesize both CD3 and CD4. The main factor in the successful synthesis is the creation of a glucopyranose ring conformationally counterbalanced between equatorial- and axial-rich forms. This suppleness is imparted by a bridge between O-3 and O-6 of glucose, which enables the generation of desirable, albeit deformed, conformers when synthesizing the cyclic trimer and tetramer.

Astroglia in Sepsis Associated Encephalopathy.

Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.

1019: Progesterone attenuates brain inflammatory response and protects the brain from inflammation-induced immature myeloid cells increase

Pregnancy is a challenge for the maternal immune system since it has to defend against pathogens while tolerating alloantigenic fetal tissue. Little is known about maternal brain immune system during pregnancy. During pregnancy there is a marked increase in endogenous progesterone (PRO) and PRO supplementation is used for prevention of preterm birth. We sought to determine the maternal brain immune response to inflammation in pregnant (P) and non-pregnant (NP) mice and whether PRO supplementation attenuates this response. NP & P mice were pretreated with vaginal PRO or carrier from E13-E16. Lipopolysaccharide (LPS 30μg) or vehicle were administered intraperitoneally at E15 & E16. Serum was analyzed for IL-6 levels by ELISA. Brain was analyzed for nNOS, NFkB, IL-6 & TNF-a levels by western blot. Brain immature myeloid cells (IMC; CD45high, CD11b+, Gr1+) as % of CD45high hematopoietic brain cells and microglial (CD45low cells) activity as medial CD45 intensity was analyzed by FACS. LPS significantly increased brain nNOS, NFkB, IL-6 & TNF-a protein brain levels in NP & P mice. PRO pretreat ment significantly reduced nNOS and NFkB brain levels following LPS treatment in both groups. In NP mice, LPS treatment significant increased brain IMC population, and PRO pretreatment reduced the increase. In P mice, neither LPS nor LPS & PRO altered the brain IMC population. LPS led to a significant increase in microglial activity both groups. PRO pretreatment led to significant decrease in microglial activity in P mice. In NP mice, there was a trend but it did not reach statistical significance. PRO had no effect on serum IL-6 levels in both groups. PRO attenuates the inflammatory response in the brain in NP & P mice but had no effect on systemic (IL-6) inflammation. LPS increased brain IMC population in NP mice but not in P mice and PRO pretreatment reduced the IMC increase. These results suggest that endogenous PRO during pregnancy may protect the brain from LPS-induced central inflammation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Placental Macrophages: A Window Into Fetal Microglial Function in Maternal Obesity

Fetal placental macrophages and microglia (resident brain macrophages) have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living fetus or neonate is impossible. We sought to test the hypothesis that maternal obesity would prime both placental macrophages and fetal brain microglia to overrespond to an immune challenge, thus providing a window into microglial function using placental cells.Obesity was induced in C57BL/6 J mice using a 60% high-fat diet. On embryonic day 17.5, fetal brain microglia and corresponding CD11b + placental cells were isolated from fresh tissue. Cells were treated with media or lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-α) production by stimulated and unstimulated cells was quantified via ELISA. We demonstrate for the first time that the proinflammatory cytokine production of CD11b + placental cells is strongly correlated with that of brain microglia (Spearman’s ρ = 0.73, p = 0.002) in the setting of maternal obesity. Maternal obesity-exposed CD11b + cells had an exaggerated response to LPS compared to controls, with a 5.1-fold increase in TNF-α production in placentas (p = 0.003) and 3.8-fold increase in TNF-α production in brains (p = 0.002). In sex-stratified analyses, only male obesity-exposed brains and placentas had significant increase in TNF-α production in response to LPS. Taken together, these data suggest that maternal obesity primes both placental macrophages and fetal brain microglia to overproduce a proinflammatory cytokine in response to immune challenge. Male brain and placental immune response is more marked than female in this setting. Given that fetal microglial priming may impact neuroimmune function throughout the lifespan, these data could provide insight into the male predominance of certain neurodevelopmental morbidities linked to maternal obesity, including cognitive dysfunction, autism spectrum disorder, and ADHD. Placental CD11b+ macrophages may have the potential to serve as an accessible biomarker of aberrant fetal brain immune activation in maternal obesity. This finding may have broader implications for assaying the impact of other maternal exposures on fetal brain development.

Blood-derived plasminogen drives brain inflammation and plaque deposition in a mouse model of Alzheimer’s disease

Two of the most predominant features of the Alzheimer's disease (AD) brain are deposition of β-amyloid (Aβ) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate the deposition of Aβ. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through α-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain's immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development.

Dcf1 Deficiency Attenuates the Role of Activated Microglia During Neuroinflammation.

Microglia serve as the principal immune cells and play crucial roles in the central nervous system, responding to neuroinflammation via migration and the execution of phagocytosis. Dendritic cell-derived factor 1 (Dcf1) is known to play an important role in neural stem cell differentiation, glioma apoptosis, dendritic spine formation, and Alzheimer’s disease (AD), nevertheless, the involvement of the Dcf1 gene in the brain immune response has not yet been reported. In the present paper, the RNA-sequencing and function enrichment analysis suggested that the majority of the down-regulated genes in Dcf1-/- (Dcf1-KO) mice are immune-related. In vivo experiments showed that Dcf1 deletion produced profound effects on microglial function, increased the expression of microglial activation markers, such as ionized calcium binding adaptor molecule 1 (Iba1), Cluster of Differentiation 68 (CD68) and translocator protein (TSPO), as well as certain proinflammatory cytokines (Cxcl1, Ccl7, and IL17D), but decreased the migratory and phagocytic abilities of microglial cells, and reduced the expression levels of some other proinflammatory cytokines (Cox-2, IL-1β, IL-6, TNF-α, and Csf1) in the mouse hippocampus. Furthermore, in vitro experiments revealed that in the absence of lipopolysaccharide (LPS), the majority of microglia were ramified and existed in a resting state, with only approximately 10% of cells exhibiting an amoeboid-like morphology, indicative of an activated state. LPS treatment dramatically increased the ratio of activated to resting cells, and Dcf1 downregulation further increased this ratio. These data indicated that Dcf1 deletion mediates neuroinflammation and induces dysfunction of activated microglia, preventing migration and the execution of phagocytosis. These findings support further investigation into the biological mechanisms underlying microglia-related neuroinflammatory diseases, and the role of Dcf1 in the immune response.

Depresioaren teoria neuroinflamatorioa

Depresio nagusia asaldura neuropsikiatriko ohikoenen artean dago. Gaixotasun mental honen etiologia eta oinarri fisiopatologikoak azaltzeko hainbat teoria proposatu dira, hala nola teoría monoaminergikoa edo neurotrofikoa. Hala ere, oinarri neurobiologikoak oraindik ez dira ezagutzen, sistema ezberdinen parte-hartzea izanik proposatzen dena. Depresioan hanturaren eta funtzio neuralaren arteko elkarrekintza dagoela frogatzen duten entsegu prekliniko eta klinikoetako emaitzak gero eta pisu handiagoa hartzen ari dira, teoría neuroinflamatorioa indartuz. Horrek proposatzen du depresioan sistema ezberdinetan asaldurak gertatuko liratekeela: ardatz hipotalamiko-hipofisiario-adrenalaren (HPA) hiperaktibazioa (igotako glukokortikoide-mailak eraginez) bai eta sistema immunearen hiperaktibazioa ere, periferiako eta nerbio-sistema zentraleko (NSZ) hanturaren markatzaileen, hau da, zitokina proinflamatorioen mailak handituz. Gainera, depresiodun pazienteetan aurkitu diren periferiako gehiegizko zitokinak garunera igarotzeko gai direla eta depresioan ezagunak diren bide fisiopatologiko gehienei eragiten dietela deskribatu da. Horien artean neurotransmisoreen metabolismoa, funtzio neuroendokrinoa eta plastikotasun edo moldatze neurala daude. Hain zuzen ere, garuneko hanturaren aktibazioak depresioan gertatzen diren asaldura fisiopatologikoen antzeko moldaketak eragiten ditu, faktore neurotrofikoen gutxipena, eszitotoxikotasuna eta horren ondorio den estres oxidatiboa, adibidez. Areagotutako zitokinen kalte kronikoak iraupen luzeko aldaketak dakartza garunaren anatomian eta funtzionamenduan, eta kalteok umorean, kognizioan edo portaeran eragin zuzena izango dute. Hortaz, garunaren endekapen hau sintoma depresiboekin lotzea funtsezkoa da tratamendua aukeratzeko orduan. Izan ere, gaixotasun inflamatorioak dituzten pazienteetan lortutako emaitzen arabera, zitokina proinflamatorioak inhibitzeak gaixoek pairatzen dituzten sintoma depresiboak hobetzen eta pazientearen ohiko tratamendu antidepresiboaren erantzuna hobetzen lagundu dezake. Beraz, garunean gertatzen den hantura eta sistema immunea itu dituzten tratamenduak garatzea aukera bat izan daiteke hantura duten depresiodun pazienteen sintomatologia hobetzeko.