Alzheimer’s disease hypothesis and related therapies

Translational Neurodegeneration, Год журнала: 2018, Номер 7(1)

Опубликована: Янв. 24, 2018

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia. There are many hypotheses about AD, including abnormal deposit of amyloid β (Aβ) protein in extracellular spaces neurons, formation twisted fibers tau proteins inside cholinergic neuron damage, inflammation, oxidative stress, etc., anti-AD drugs based on these have been developed. In this review, we will discuss existing emerging hypothesis related therapies.

Язык: Английский

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Microglia monitor and protect neuronal function through specialized somatic purinergic junctions

Science, Год журнала: 2019, Номер 367(6477), С. 528 - 537

Опубликована: Дек. 13, 2019

Microglia are the main immune cells in brain and have roles homeostasis neurological diseases. Mechanisms underlying microglia-neuron communication remain elusive. Here, we identified an interaction site between neuronal cell bodies microglial processes mouse human brain. Somatic junctions a specialized nanoarchitecture optimized for purinergic signaling. Activity of mitochondria was linked with junction formation, which induced rapidly response to activation blocked by inhibition P2Y12 receptors. Brain injury-induced changes at somatic triggered receptor-dependent neuroprotection, regulating calcium load functional connectivity. Thus, these could potentially monitor protect functions.

Язык: Английский

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Sex-Specific Features of Microglia from Adult Mice

Cell Reports, Год журнала: 2018, Номер 23(12), С. 3501 - 3511

Опубликована: Июнь 1, 2018

Sex has a role in the incidence and outcome of neurological illnesses, also influencing response to treatments. Neuroinflammation is involved onset progression several diseases, fact that estrogens have anti-inflammatory activity suggests these hormones may be determinant sex-dependent manifestation brain pathologies. We describe significant differences transcriptome adult male female microglia, possibly originating from perinatal exposure sex steroids. Microglia isolated brains maintain sex-specific features when put culture or transplanted opposite sex. Female microglia are neuroprotective because they restrict damage caused by acute focal cerebral ischemia. This study therefore provides insight into distinct perspective on mechanisms underscoring sexual bias susceptibility diseases.

Язык: Английский

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Imaging the evolution and pathophysiology of Alzheimer disease

Nature reviews. Neuroscience, Год журнала: 2018, Номер 19(11), С. 687 - 700

Опубликована: Сен. 28, 2018

Язык: Английский

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Single-cell analysis reveals T cell infiltration in old neurogenic niches

Nature, Год журнала: 2019, Номер 571(7764), С. 205 - 210

Опубликована: Июль 3, 2019

Язык: Английский

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A Combination of Ontogeny and CNS Environment Establishes Microglial Identity

Neuron, Год журнала: 2018, Номер 98(6), С. 1170 - 1183.e8

Опубликована: Июнь 1, 2018

Язык: Английский

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Microglial subtypes: diversity within the microglial community

The EMBO Journal, Год журнала: 2019, Номер 38(17)

Опубликована: Авг. 2, 2019

Review2 August 2019Open Access Microglial subtypes: diversity within the microglial community Vassilis Stratoulias orcid.org/0000-0002-9724-6589 Toxicology Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Search for more papers by this author Jose Luis Venero Departamento de Bioquímica y Biología Molecular, Facultad Farmacia, Universidad Sevilla, Spain Instituto Biomedicina Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad Marie-Ève Tremblay Department Molecular Université Laval, Quebec, QC, Canada Axe Neurosciences, Centre Recherche du CHU Québec-Université Bertrand Joseph Corresponding Author [email protected] orcid.org/0000-0001-5655-9979 Information Stratoulias1, Venero2,3, Tremblay4,5 and *,1 1Toxicology 2Departamento 3Instituto 4Department 5Axe *Corresponding author. Tel: +46 703057405; E-mail: The EMBO Journal (2019)38:e101997https://doi.org/10.15252/embj.2019101997 PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Microglia are brain-resident macrophages forming first active immune barrier in central nervous system. They fulfill multiple functions across development adulthood under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure extrinsic cues their environment. However, emerging evidence suggests that display differences not exclusively driven milieu, rather unique properties these cells possess. This intrinsic heterogeneity has been largely overlooked, favoring prevailing view a single-cell type endowed with spectacular plasticity, allowing them acquire thereby numerous health disease. Here, we review might form which each member (or "subtype") displays performs functions. Distinctive features functional implications several subtypes considered, contexts Finally, suggest subtype categorization shall be based on function propose ways studying them. Hence, advocate plasticity (reaction states) (subtypes) should both considered when multitasking microglia. Introduction were introduced scientific literature century ago (Río-Hortega, 1919a,1919b,1919c; Fig 1). During normal physiological conditions, ramified morphology regularly distributed throughout system (CNS; Río-Hortega, 1919b). Upon pathology, transform function, leading cascade "reaction" from hypertrophic ameboid still orients research today (Flanary et al, 2007; Graeber, 2010; With recent advances genetic tools fate mapping (Ginhoux 2010), now tissue-resident CNS arise embryonic yolk sac (Alliot 1999; Schulz 2012; Kierdorf 2013; Perdiguero 2015). colonize murine day (E)9.5 (Tay 2017c) represent self-maintaining long-lived cell population persists months, if entire lifespan organism (Lawson 1992; Ajami 2007, 2011; Mildner Askew 2017; Füger Réu Tay 2017b). Beyond functioning as mediators injury, inflammation, neurodegeneration, roles healthy brain have identified at an exponential rate past decade (Cartier 2014; 2015; Figure 1. Historical overview identificationAlthough originally proposed Rio-Hortega report microglia, it was only recently idea revisited. Download figure PowerPoint exhibit widely differing depending stage life, region, context or Differences number, morphology, gene expression also reported between sexes (Schwarz Crain Lenz Pimentel-Coelho Butovsky Dorfman Hanamsagar Krasemann 2017). Adequate crucial behavioral adaptation environment (Salter Stevens, 2017a). Throughout contribute neurogenesis, neuronal circuit shaping, vascular formation remodeling, maintenance homeostasis 2017c). aging diseases, may become reactive impaired surveillance phagocytosis (Streit, 2002; Koellhoffer Spittau, contribution diseases is associated compromised (e.g., synaptic plasticity; 2017a) processes adaptive brain, yet death tissue damage pathological settings excitotoxicity, oxidative stress, inflammation; Weil 2008). reaction can triggered any kind insults disturbances CNS. Persisting reaction, often proliferation, involved conditions ranging neurodevelopmental disorders, traumatic injuries, infectious tumors, psychiatric neurodegenerative diseases. Depending stressor insult play, process shown proceed differently result sometimes contrasting outcomes (see 2A classical schematic representation, depicting gray surrounded palette colorful representing state). It recognized wide range states, tremendous shift M1/M2 classification used few years (Martinez Gordon, Ransohoff, 2016). According view, would fulfilled through toward phenotypes, molecular signature (Crain Hickman Bennett 2016; Grabert Flowers Galatro Keren-Shaul Hammond 2018; Masuda 2019). pieces indicate different pools acquired during maturation These co-exist steady state undergo further modulation phenotypic transformation response stimuli (Fig 2B). Indeed, beyond adopts stimuli, constitute members properties, perform functions, respond 2C). We distinctive putative "subtypes", structural, ultrastructural, levels, well Furthermore, categorize than signatures markers. candidates validated using methodological workflow recommend. 2. states(A) Currently, homogenous cellular (core circle gray) extremely plastic. status given developmental resulting invariably assume described literature. (B) In updated version here, heterogeneous having specializations. (C) environmental cue, stimulus, expanding and/or changing its specific phenotype. Microglia: fulfilling vast What defines subject intense debate, discussed Box 1 Accumulating indicates naïve responds identically possible assuming predetermined fact, historical perspective, notion had already 1919 his original description 1919b; He noticed some he named "satellite" found close proximity bodies. A later, satellite below, one playing cards deck 3). important acknowledge others, avant-garde scientists, paved way concept (McCluskey Lampson, 2000; Olah Hanisch, Gertig 2014). 1: How define "cell (sub)type" answer "how subtype?" probably closely related question, type?" Traditionally, defined host tissue, lineage, composition. definition term remains debate (Clevers advancement unbiased technologies transcriptome profiling, such high throughput RNAseq mass cytometry improved/related methods), revealed remarkable among traditionally homogeneous. whereas degree proteome sufficient defining subtypes, even topic (Trapnell, Okawa 2018). While allow molecularly subpopulations, approaches require complemented identification populations, order those (sub)types. Worth notice, importance confound states reaction. latter referring various stimuli. shared properties/characteristics other type. Their selective independent microenvironment. two concepts mutually exclusive, stimulus could react new phenotype, i.e., thus adding another level complexity. must steady-state unchallenged propertie(s) translate into function(s). Typically, existing foundation plan, biased respect studies aimed identifying subtype. includes work markers, most importantly staining, sorting, isolation cells. Reverse provide reliable tool studies, but they inherit technical limitations gating flow antibody unspecificity (Luo 2013). On hand, RNAseq, cytometry, electron microscopy useful tools, aware limitation terms providing static dynamics. however combined two-photon vivo imaging insights Serendipitous approach, sporadic non-systematic. All above methodologies subtypes. Considering review, need classifying evident. Deciphering whether variations instructed microenvironment prime importance, following workflow: Fate-mapping strategies visualize selectively subsets, instance non-invasive chronic imaging—could performed longitudinally development, adulthood, aging, conditions—to determine identity subsets phenotypes. remain examined longitudinally, instead another, notably determinants then studied combination protein analyses, ultrastructure, dynamic investigations. 3. Putative specializationsEmerging data support existence genomic, spatial, morphological, anticipate analyzing thoroughly, 1, similar methodology newly discovered ones, will number characteristics targeted prevention treatment. regional Although ubiquitously scattered CNS, distribution varies regions, white matter 1990). differs presence bodies, dendrites axons, myelinated blood vessels. self-renewal turnover rates lipopolysaccharide (LPS) challenge 2017b; Furube tightly transcriptional level, mouse human (Gosselin 2014, Direct variability comes isolated wild-type, adult mice, according area, determined panels pre-selected study, CD11b, CD40, CD45, CD80, CD86, F4/80, TREM2b, CX3CR1, CCR9 compared regions young mice (de Haas all markers expressed varied significantly areas. study rats, levels known showed region-specific profiles (Doorn Similar areas additionally pattern (Butovsky De Biase Additionally, RNA sequencing (RNAseq) cerebral hippocampal analyzed, 47 identified, including belonging (Zeisel findings raise intriguing possibility survival, activity, growth factor release, metabolism, myelination, blood–brain driving differentiation major contributing heterogeneity. Recently, cerebellar clearance ability, genes supporting engulfment catabolism debris (Ayata "type" reminiscent developing disease-associated (DAM) below. By contrast, striatum homeostatic epigenetic mechanisms particular, suppression striatal mediated PRC2, catalyzes repressive chromatin modification histone H3 lysine 27 trimethylation (H3K27me3). ablation PRC2 results emergence absence dying neurons, cortex. aberrant induce motor responses, decreased learning memory, together anxiety seizures characterized CNS-associated (CAM) three CAM Mrc1, Ms4at, Pf4, Stab1, Cbr2, CD163, Fcrls, compartments: leptomeninges, choroid plexus, perivascular space (Jordão Consequently, partly accounted diversity. differential expressions Differential established approach subpopulations type, GABAergic glutamatergic) observed brain. contexts, neighboring state. local cues, interactions neurons inhibitory excitatory) glial (astrocytes, oligodendrocytes, progenitors), slight signaling thresholds. Similarly, peripheral macrophage activation LPS viruses described, where subset concomitantly (Ravasi 2002). addition, directly communicate other, recruitment lead inhibition initially occupying non-overlapping territories changing, improved staining methods showing direct contacts bodies neighbor (for example, see Milior marker adjacent previous challenges considered. For instance, laser injury intact, converging site (Nimmerjahn 2005; Paris migrate cortex (Eyo 2018) cerebellum (Stowell paints layer expression, cannot excluded argue deserves investigation. below: Keratan sulfate proteoglycan (KSPG)-microglia quarter ago, rat constitutive KSPG (Bertolotto 1993), visualized situ 5D4 monoclonal located extracellular matrix surface. suggested control adhesion axonal growth. 5D4-KSPG subpopulation contrary 1993, 1998). Of note, does coincide GFAP, NG2, MAP2, relate strains inbred rats (Jander Stoll, 1996b). mammals, 5D4-KSPG-expressing spinal cord retina 1998; Jander 1996a; Jones Tuszynski, Zhang Foyez 5D4-KSPG-microglia preferential large numbers hippocampus, brainstem, olfactory bulb (OB), detected neonatal mention 5D4-KSPG-negative same (Jones KSPG-reactivity, systematic required confirm 4). 4.Toolbox. Hox8b-microglia differentiates canonical population, spatial temporal 2 ontogeny Hoxb8-microglia). Mice carrying driver Hoxb8-Cre reporter ROSA26-YFP alleles crossed trace YFP-Hoxb8 expression. YFP signal appeared YFP-positive especially OB (Chen 25–40% total YFP-negative Nagarajan Transcriptomic analyses comparing Hoxb8-positive Hoxb8-negative very state, 21 populations (De Hoxb8-microglia express genes, Tmem119, Sall1, Sall3, Gpr56, Ms4a7, hematopoietic Clel12a, Klra2, Lilra5 non-Hoxb8 (Bennett neither expresses Hoxb8 brain; instead, lineage tracer progenitors prior infiltration Selective inactivation grooming behavior, mutant strategy deletion included use Tie2 Cre affect endothelial 2010). More cell-specific prerequisite involvement behavior. (with illustration): Revisiting origin(s) An question arising relates origin(s). Do possess populating do once assumed parenchyma? convincingly derive wave hematopoiesis Hoeffel Sheng Mass 2016), follow stepwise program (Mass Matcovitch-Natan before E9.5 Based literature, differentiate inside parenchyma (a). hypothesis explain microenvironments (inhibitory, oligodendrocytes thresholds, alternative exhibiting infiltrating early investigation, tested (b c). later hypothesis, Capecchi al Hoxb8-microglia-progenitors exist E8.5 Subsequently, transit aorta-gonad-mesonephros fetal liver, expand entry E12.5 (c). lines, CSF1R−/− Erblich 2011) IL2-Tgfb1;Tgfb1−/− (Keren-Shaul 2017) transgenic expected parenchyma. E14.5 exist, Ms4a7 (Hammond great interest investigate subpopulations. zebrafish, waves (Xu Ferrero yolk-sac-equivalent structure origin populate replenished zebrafish (d). div

Язык: Английский

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Gut Microbiota–Derived Short-Chain Fatty Acids Promote Poststroke Recovery in Aged Mice

Circulation Research, Год журнала: 2020, Номер 127(4), С. 453 - 465

Опубликована: Май 1, 2020

The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, potential benefits manipulating microbiome injury is unknown. To determine if restoring youthful microbiota aids in recovery aged subjects, we altered through young fecal transplant gavage mice experimental stroke. Further, effect direct enrichment selective bacteria producing short-chain fatty acids (SCFAs) was tested as a targeted refined therapy. Aged male (18-20 months) were subjected ischemic middle cerebral artery occlusion. We performed 3 days occlusion using donor biome (2-3 or months). At day 14 receiving had less behavioral impairment, reduced brain inflammation. Based on data from microbial sequencing metabolomics analysis demonstrating transplants contained much SCFA levels related bacterial strains, selected 4 SCFA-producers (Bifidobacterium longum, Clostridium symbiosum, Faecalibacterium prausnitzii, Lactobacillus fermentum) for transplantation. These alleviated poststroke neurological deficits inflammation, elevated gut, plasma concentrations mice. This first study suggesting poor reversed via bacteriotherapy following replenishment modulation immunologic, microbial, metabolomic profiles host.

Язык: Английский

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Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(9), С. 2293 - 2293

Опубликована: Май 9, 2019

A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter expression plethora inflammatory mediators. These factors, in turn, initiate or contribute development processes. an important tool for study However, serotype, route administration, number injections this toxin induce varied responses. Thus, here, we review use models neurodegeneration well discuss neuroinflammatory mechanisms induced by could underpin events linked process.

Язык: Английский

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Converging pathways in neurodegeneration, from genetics to mechanisms

Nature Neuroscience, Год журнала: 2018, Номер 21(10), С. 1300 - 1309

Опубликована: Сен. 19, 2018

Язык: Английский

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