Astrocytes, neurons, synapses: a tripartite view on cortical circuit development

Neural Development, Journal Year: 2018, Volume and Issue: 13(1)

Published: April 30, 2018

In the mammalian cerebral cortex neurons are arranged in specific layers and form connections both within with other brain regions, thus forming a complex mesh of specialized synaptic comprising distinct circuits. The correct establishment these during development is crucial for proper function brain. Astrocytes, major type glial cell, important regulators synapse formation development. While neurogenesis precedes astrogenesis cortex, neuronal synapses only begin to after astrocytes have been generated, concurrent branching process elaboration. Here we provide combined overview developmental processes circuit rodent emphasizing timeline astrocytic maturation. We further discuss role at synapse, focusing on astrocyte-synapse contact synapse-related proteins promoting cortical

Language: Английский

---

Systemic inflammation impairs microglial Aβ clearance through NLRP 3 inflammasome

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(17)

Published: July 30, 2019

Article30 July 2019Open Access Transparent process Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome Dario Tejera Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospitals Bonn, Germany German Center for Diseases (DZNE), Search more papers by this author Dilek Mercan Juan M Sanchez-Caro Mor Hanan Biological Chemistry, The Alexander Silberman Institute Life Sciences, Hebrew Jerusalem, Israel David Greenberg Hermona Soreq orcid.org/0000-0002-0955-526X Eicke Latz Infectious Immunology, Massachusetts Medical School, Worcester, MA, USA Innate Immunity, Douglas Golenbock Michael T Heneka Corresponding Author [email protected] orcid.org/0000-0003-4996-1630 Information Tejera1,2,‡, Mercan1,‡, Sanchez-Caro1, Hanan3, Greenberg3, Soreq3, Latz2,4,5, Golenbock4 *,1,2,4 1Department 2German 3Department 4Department 5Institute ‡These authors contributed equally to work *Corresponding author. Tel: +49 228 28713091; Fax: 28713166; E-mail: EMBO Journal (2019)38:e101064https://doi.org/10.15252/embj.2018101064 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Alzheimer's disease is most prevalent type dementia caused deposition extracellular amyloid-beta abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing brain's major innate immune cells, play important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized retraction cell processes. known increase risk cognitive decline human neurogenerative diseases Here, we assess first time upon peripheral challenge context aging vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 10 days post-challenge lipopolysaccharide. exhibited reduction number branches area covered days, phenomenon that resolved days. reduced APP/PS1 mice. knockout blocked many observed lipopolysaccharide, alterations morphology amyloid pathology. inhibition may thus represent novel therapeutic target protect brain from toxic systemic infection. Synopsis negatively regulated NLRP3-dependent fashion. Collectively, these results shed light on mechanism underlying Alzheimer progress aggravation inflammation. activates transient manner. clearance. but not APP/PS1xNLRP3ko mice accelerated challenge. Collectively data suggest driven cerebral amyloidosis. Introduction Traditionally, been conceived immune-privileged organ. However, it now widely accepted several factors obesity, acute injuries, aging, neurodegenerative can trigger sustained response central nervous system (CNS) leading neuronal dysfunction demise activation release neuroinflammatory mediators (Lucin Wyss-Coray, 2009; Villeda et al, 2014; 2015). (AD) affecting approximately 45 million people worldwide. Pathologically, AD amyloid-β (Aβ), formation neurofibrillary tangles neuroinflammation (Heneka 2014). hypothesis contributes pathogenesis recently supported genome-wide association studies which have identified immune-related gene variants, Trem2 (Guerreiro 2013) Cd33 (Bradshaw 2013), modify developing AD. Under physiological conditions, microglia, resident cells CNS, exhibit highly ramified motile processes allow continued surveillance environment tissue damage, debris, or pathogens. sense signals indicating such challenges, they react order maintain homeostasis (Davalos 2005; Tremblay 2010). During neurodegeneration, acquire activated phenotype, morphologically branch accompanied soma volume. Functionally, defined pro-inflammatory cytokines IL-1β, TNF-α, IL-6 (Biber 2007; Wyss-Coray Rogers, 2012; Heneka, 2016). initiation inflammatory involves multiprotein complexes termed "inflammasomes". Comprising cytosolic platform, enables caspases, mainly caspase-1. NACHT-, LRR-, pyrin (PYD)-domain-containing protein 3 (NLRP3) best-characterized implicated regulator IL-1β IL-18 (Lu Walsh In AD, are fibrillar presumably attempt remove aggregates. It shown dependent (Halle 2008; 2013). Because early event, preceding development mnestic deficits years if decades (Jack likely influences clinically silent period. therefore identify exogenous endogenous influence thereby There considerable evidence suggesting triggers response, with deleterious consequences learning memory rodent models (Semmler 2005, Weberpals 2009) patients (Qin Semmler 2008, 2013; Iwashyna 2010; Gyoneva Widmann Additionally, proposed could different (AD), Parkinson's disease, multiple sclerosis (Cunningham Qin Cardoso While microglia-driven key inflammation, diseases, its dynamics vivo remain poorly understood. two-photon microscopy (2PLSM), describe effects activation. Moreover, determine how alters pathology regulating capacity. On mechanistic level, inflammasome-signaling pathway mediator detrimental Results affects age-dependent manner Previous reports demonstrated administration single dose lipopolysaccharide (LPS) ranging (0.5–1 mg/kg) septic shock dosages (5–10 causes 2014), identifying affected Using 2PLSM, sought behind changes. Hence, performed cranial window surgery 15-month-old (mo) Cx3cr1-eGFP−/+ weeks later injected them bacterial wall component LPS (1 mg/kg i.p). Following challenge, assessed within 48 h post-LPS. 2PLSM revealed 24 after injection, showed morphological signs activation, significant number, length, maximum when compared control (Fig 1A B). found peaked h, 50% all parameters measured To whether permanent nature also priming factor (Cunningham, Raj Fonken 2016), results, 5-month- analyzed longitudinally post-LPS 1C). Comparison between 5 15mo animals already presented 1D E) prior any administration, was well length E). addition, consequence above-described branches, volume (total length/cell volume) significantly 5mo absence age compromised surveying functions already. As mice, had Interestingly, there injection case no parameters, indistinguishable baseline conditions corroborate marker CD68 (Hickman evaluated immunohistochemistry. A immunoreactivity EV1). Importantly, levels same PBS-treated Figure 1. transiently Representative 3D reconstructions showing h. Scale bar: μm. Morphological quantification (mean 5–6 ± SEM; one-way ANOVA followed Tukey's post hoc test, *P < 0.05, **P 0.01, ***P 0.001). Two-photon experimental design. 5- injection. 20 two-way #*P Download figure PowerPoint Click here expand figure. EV1. Transient staining cortex 15 months old wild-type Nlrp3−/− integrated density ko refractory age-associated Inflammasomes form microbial danger signals, leads cleavage pro-caspase-1 into active caspase-1 enzyme. Active then cleaves pro-forms cytokines, IL-18, forms (Vanaja 2015; Man involved crossed 2A). No differences Nlrp3 deficiency protects against age-induced 2B C). C), since tested points line findings, 2. Nlpr3 Schematic representation representative images (5 old). Quantification Nlpr3−/− 5-6 0.01). subsequent requires adaptor ASC, turn recruitment effector (Baroja-Mazo Interaction ASC lead speck (Venegas 2017). We specks concordant (Appendix Fig S1A). Notably, S1A mention inflammasome, detectable Accordingly, EV2A), whereas then, consistent return basal When TNF-α measured, groups, EV2A). transient; Remarkably, liver, measurement mirrored higher both EV2B). EV2. periphery ELISA lysates Nlrp3−/−. levels. For groups 6 liver triggered Astrocytes CNS participate myriad processes, providing trophic support neurons promoting synapse elimination (Jäkel Dimou, subset astrocytes become reactive (Liddelow Considering plausible imagine undergo astrocytosis. Indeed, increased GFAP EV3A B) both, similar described, B), corroborating required promote EV3. cortical pictures stained GFAP. Peripheral Since represents neurodegeneration particularly (for review see: 2015), hallmarks mediated inflammasome. Therefore, APP/PS1/Nlrp3−/− underwent protocols described above non-APP/PS1 size deposits 3A B, Appendix S2A 15mo, APP/PS1/Nlrp3/− investigated At 5mo, begin appear model, apparent (Maia These confirmed measurements Aβ1–40 Aβ1–42 3B). Of note, modification APP processing machinery S2C D). S1B previously 2017), observations appeared be NLRP3-dependent, Together, elicited aged 3. MXO4 APP/Nlrp3−/− 50 Cortical plaque quantification, Amyloid-beta1–40 1–42 (5- 15-month-old) 8 depend distance cluster around being retracted less dynamic plaque-free distant (Condello This suggests functional least two populations distinguished location murine models, those located near Aβ, distantly located. Analysis did further vicinity 4A 60 μm radius deposit core. observation due existing high-level itself S3). impaired uptake 4C D, S4). sense, presence proofed determinant factor, interaction strain (F = 6.44. DFn DFd 13 P value 0.014). Altogether, status capacity cells. 4. (eGFP) clustering (A) SEM). Flow cytometry plots (15 old), gated CD11b isolation. Relative 0.05). beclin-1 demonstrated, would affect expression present study, decreased challenged EV4). EV4. Western blot analysis whole lysate antibody. 2–5 contrast plaque-associated plaque-distant reminiscent respect time-dependent age, post-LPS, recovery 5A (15mo) despite direct contact deposits, soluble species factors, render responsive stimulation. Nlrp3−/−, largely 5. areas free mice). myeloid infiltrate brains Myeloid infiltration occurs (Wohleb Jay Lévesque 2016; Wattananit investigate phenomenon, sections immunostained Iba-1 CD169 (Rice Perez 2017; Shinde 2018). suggested specific bone marrow-derived monocytes help differentiate infiltrating (Butovsky 2012). young WT reveal S5A Similarly, induce S5C Likewise, immunopositive LPS. strong contrast, CD169-positive became aged, mostly close depo

Language: Английский

---

Astrocyte Biomarkers in Alzheimer’s Disease

Trends in Molecular Medicine, Journal Year: 2019, Volume and Issue: 25(2), P. 77 - 95

Published: Jan. 2, 2019

Language: Английский

---

Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(9)

Published: July 22, 2021

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation microglia. Because variants genes expressed in microglia correlate with AD risk, microglial response to plausibly impacts course. In mouse models, single-cell RNA sequencing (scRNA-seq) analyses delineated this as progressive conversion homeostatic into disease-associated (DAM); additional reactive populations have been reported other models neurodegeneration neuroinflammation. We review all these signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, proliferating propose that are either just one or a combination, depending on the clustering strategy applied model. further single-nucleus (snRNA-seq) data from human specimens discuss reasons for parallels discrepancies between transcriptional profiles. Finally, we outline future directions delineating impact pathogenesis.

Language: Английский

---

Astrocyte senescence promotes glutamate toxicity in cortical neurons

PLoS ONE, Journal Year: 2020, Volume and Issue: 15(1), P. e0227887 - e0227887

Published: Jan. 16, 2020

Neurodegeneration is a major age-related pathology. Cognitive decline characteristic of patients with Alzheimer's and related dementias cancer after chemo- or radio-therapies. A recently emerged driver these other pathologies cellular senescence, cell fate that entails permanent cycle arrest pro-inflammatory senescence-associated secretory phenotype (SASP). Although there link between inflammation neurodegenerative diseases, are many open questions regarding how senescence affects pathologies. Among the various types in brain, astrocytes most abundant. Astrocytes have proliferative capacity essential for neuron survival. Here, we investigated primary human made senescent by X-irradiation, identified genes encoding glutamate potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal death co-culture assays. Unbiased RNA sequencing transcripts expressed non-senescent confirmed homeostasis pathway declines Our results suggest key role particularly astrocytes, excitotoxicity, which may lead neurodegeneration including disease dementias.

Language: Английский

---

The role of astrocyte‐mediated plasticity in neural circuit development and function

Neural Development, Journal Year: 2021, Volume and Issue: 16(1)

Published: Jan. 7, 2021

Abstract Neuronal networks are capable of undergoing rapid structural and functional changes called plasticity, which essential for shaping circuit function during nervous system development. These range from short-term modifications on the order milliseconds, to long-term rearrangement neural architecture that could last lifetime organism. Neural plasticity is most prominent development, yet also plays a critical role memory formation, behavior, disease. Therefore, it define characterize mechanisms underlying onset, duration, form plasticity. Astrocytes, numerous glial cell type in human system, integral elements synapses components network can coordinate activity at circuit-wide level. Moreover, their arrival CNS late embryogenesis correlates onset sensory-evoked activity, making them an interesting target studies. Technological advancements decade have uncovered astrocytes as regulators assembly function. Here, we provide brief historical perspective our understanding review latest advances astroglia regulating development homeostasis.

Language: Английский

---

Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 17(6), P. 333 - 348

Published: April 29, 2021

Language: Английский

---

The Dialogue Between Neuroinflammation and Adult Neurogenesis: Mechanisms Involved and Alterations in Neurological Diseases

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 60(2), P. 923 - 959

Published: Nov. 16, 2022

Language: Английский

---

The Interplay between Glioblastoma and Its Microenvironment

Cells, Journal Year: 2021, Volume and Issue: 10(9), P. 2257 - 2257

Published: Aug. 31, 2021

GBM is the most common primary brain tumor in adults, and aggressive nature of this contributes to its extremely poor prognosis. Over years, heterogeneous adaptive has been highlighted as a major contributor efficacy many treatments including various immunotherapies. The challenge lies understanding manipulating complex interplay among different components within microenvironment (TME). This varies not only by type cells interacting but also their spatial distribution with TME. review highlights immune non-immune consequences f Understanding independent interdependent aspects sub-populations encapsulated will allow for more targeted therapies. Meanwhile, how TME creates responds environmental pressures such hypoxia may other multimodal approaches treatment GBM. Ultimately, better aid development advancement effective improving patient outcomes.

Language: Английский

---

Brain-on-a-chip: Recent advances in design and techniques for microfluidic models of the brain in health and disease

Biomaterials, Journal Year: 2022, Volume and Issue: 285, P. 121531 - 121531

Published: April 21, 2022

Recent advances in biomaterials, microfabrication, microfluidics, and cell biology have led to the development of organ-on-a-chip devices that can reproduce key functions various organs. Such platforms promise provide novel insights into physiological events, including mechanisms disease, evaluate effects external interventions, such as drug administration. The neuroscience field is expected benefit greatly from these innovative tools. Conventional ex vivo studies nervous system been limited by inability culture adequately mimic physiology. While animal models be used, their relevance human physiology uncertain use laborious associated with ethical issues. To date, systems developed model different tissue components brain, brain regions specific blood barrier, both normal pathophysiological conditions. still its infancy, it major impact on neurophysiology, pathology neuropharmacology future. Here, we review made limitations faced an effort stimulate next generation brain-on-a-chip devices.

Language: Английский

---