ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

Antioxidants, Journal Year: 2020, Volume and Issue: 9(8), P. 743 - 743

Published: Aug. 13, 2020

Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation neuronal damage result in the activation disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation reactive oxygen species (ROS) generation. However, mechanisms linking OS have not been well-defined; thus targeting these cells for clinical benefit has possible. In microglia, ROS generated primarily by NADPH oxidase 2 (NOX2) NOX2 is associated DAMP signalling, amyloid plaque deposition, especially cerebrovasculature. Additionally, originating from both NOX mitochondria may act second messengers propagate immune activation; intracellular signalling underlie excessive OS. Targeting key kinases inflammatory response could cease promote tissue repair. Expression antioxidant proteins dehydrogenase 1 (NQO1), promoted transcription factor Nrf2, which functions control limit Lipid droplet accumulating (LDAM) also represent double-edged sword neurodegenerative sequestering peroxidised lipids non-pathological ageing but becoming dysregulated pro-inflammatory disease. We suggest that future studies should focus on targeted manipulation understand driving inflammatory-related activation. Finally, we discuss recent evidence therapeutic target identification be unbiased founded relevant pathophysiological assays discovery translatable anti-inflammatory therapeutics.

Language: Английский

---

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Language: Английский

---

Astrocytes and Microglia: In Sickness and in Health

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(3), P. 144 - 154

Published: Feb. 7, 2020

Language: Английский

---

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

Frontiers in Cellular Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Sept. 13, 2021

Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation neuroinflammation triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation glial cells (microglia and astrocytes) widely recognized as a hallmark triggers release proinflammatory cytokines, leading to neurotoxicity neuronal dysfunction. Another feature associated with neuroinflammatory diseases impairment blood-brain barrier (BBB). The BBB, which composed brain endothelial connected tight junctions, maintains homeostasis protects neurons. Impairment this allows trafficking immune plasma proteins into parenchyma subsequent inflammatory processes brain. Besides neurons, activated also affect BBB integrity. Therefore, dysfunction can amplify act key process development neuroinflammation. integrity determined integration multiple signaling pathways within through intercellular communication between perivascular (pericytes, astrocytes, microglia, oligodendrocytes). For prevention disruption, both cellular components, such molecules cells, non-cellular mediators released should be considered. Thus, understanding intracellular that disrupt provide novel treatments for neurological In review, we discuss current knowledge regarding underlying mechanisms cells.

Language: Английский

---

Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions

Circulation Research, Journal Year: 2022, Volume and Issue: 130(8), P. 1204 - 1229

Published: April 14, 2022

Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. This review article focuses on the epidemiology, cause, mechanisms injury, current treatment strategies, future research directions ICH. Incidence hemorrhagic has increased worldwide over past 40 years, shifts in cause time as hypertension management improved anticoagulant use increased. Preclinical clinical trials have elucidated underlying ICH injury from including complex interaction between edema, inflammation, iron-induced oxidative stress. Several investigated optimal medical surgical without clear improvement survival functional outcomes. Ongoing into novel approaches for provide hope reducing effect this disease future. Areas promise therapy include prognostic biomarkers primary prevention based pathobiology, ultra-early hemostatic therapy, minimally invasive surgery, perihematomal protection against inflammatory brain injury.

Language: Английский

---

Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease

Immunity, Journal Year: 2019, Volume and Issue: 52(1), P. 167 - 182.e7

Published: Dec. 26, 2019

Language: Английский

---

Alzheimer’s Disease and Vascular Aging

Journal of the American College of Cardiology, Journal Year: 2020, Volume and Issue: 75(8), P. 942 - 951

Published: Feb. 24, 2020

Alzheimer's disease, the leading cause of dementia in elderly, is a neurodegenerative condition characterized by accumulation amyloid plaques and neurofibrillary tangles brain. However, age-related vascular changes accompany or even precede development pathology, raising possibility that they may have pathogenic role. This review provides an appraisal alterations cerebral systemic vasculature, heart, hemostasis occur disease their relationships to cognitive impairment. Although molecular pathogenesis these remains be defined, amyloid-β likely contributor brain as heart. Collectively, evidence suggests pathology dementia, including inextricably linked onset progression. Consequently, contribution factors should considered preventive, diagnostic, therapeutic approaches address one major health challenges our time.

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

---

Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Nature, Journal Year: 2021, Volume and Issue: 593(7858), P. 255 - 260

Published: April 28, 2021

Language: Английский

---

Plasma biomarkers of astrocytic and neuronal dysfunction in early‐ and late‐onset Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2019, Volume and Issue: 16(4), P. 681 - 695

Published: Dec. 24, 2019

We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD LOAD).

Language: Английский

---