Role of neuroinflammation in neurodegeneration development

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июль 12, 2023

Abstract Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s so on, have suggested that inflammation is not only a result of neurodegeneration but also crucial player this process. Protein aggregates which are very common pathological phenomenon can induce neuroinflammation further aggravates protein aggregation neurodegeneration. Actually, even happens earlier than aggregation. Neuroinflammation induced by genetic variations CNS cells or peripheral immune may deposition some susceptible population. Numerous signaling pathways range been to be involved the pathogenesis neurodegeneration, although they still far from being completely understood. Due limited success traditional treatment methods, blocking enhancing inflammatory considered promising strategies for therapy many them got exciting results animal models clinical trials. Some them, few, approved FDA usage. Here we comprehensively review factors affecting major pathogenicity sclerosis. We summarize current strategies, both clinic, diseases.

Язык: Английский

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Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Апрель 7, 2022

It has been noticed in recent years that the unfavorable effects of gut microbiota could exhaust host vigor and life, yet knowledge theory are just beginning to be established. Increasing documentation suggests microbiota–gut–brain axis not only impacts brain cognition psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), multiple sclerosis (MS). How blood–brain barrier (BBB), a machinery protecting central nervous system (CNS) from systemic circulation, allows risky factors derived translocated into seems paradoxical. For unique anatomical, histological, immunological properties underpinning its permeable dynamics, BBB regarded biomarker associated with neural pathogenesis. The permeability mice rats caused by GM dysbiosis raises question how metabolites change causes pathophysiology neuroinflammation neurodegeneration (NF&ND) aging, pivotal multidisciplinary field tightly immune chronic inflammation. If all, microbiota-induced inflammation (GM-SCI) mainly refers excessive mucosal immunity dysregulation, which is often influenced dietary components age, produced at interface intestinal (IB) or exacerbated after IB disruption, initiates various common diseases along dispersal routes, eventually impairs integrity cause NF&ND aging. To illustrate roles affected inflammatory “leaky” resulting their metabolites, we reviewed selected publications, including role barrier, influences on permeability, NF&ND, add depth bridging inflammation, plausible mechanism indispensable for corruption was highlighted; namely, maintenance cues cytokines, may help understand play major

Язык: Английский

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Cytokines in CAR T Cell–Associated Neurotoxicity

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Дек. 16, 2020

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium language dysfunction to seizures, coma, fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated (ICANS). In this review, we draw an arc our current understanding how systemic local cytokine release act on the CNS, toward possible preventive approaches. We systematically review reported correlations secreted inflammatory mediators in serum/plasma cerebrospinal fluid risk ICANS receiving CAR cell therapy. Possible pathophysiologic impacts CNS are covered detail most promising candidate cytokines, including IL-1, IL-6, IL-15, GM-CSF. To insight into final common pathways inflammation, place context other conditions that associated neurologic dysfunction, sepsis-associated encephalopathy, malaria, thrombotic microangiopathy, infections, hepatic encephalopathy. then what known about interaction components neurovascular unit, endothelial cells, pericytes, astrocytes, microglia neurons respond challenges. Current approaches, corticosteroids blockade IL-1 IL-6 signaling, reviewed role cytokines ICANS. Throughout, point out gaps knowledge approaches investigation mechanism, prevention, treatment

Язык: Английский

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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss

Circulation Research, Год журнала: 2020, Номер 128(4)

Опубликована: Дек. 30, 2020

Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described several brain disorders, genetically induced pericyte deficiency the leads to increased macromolecular leakage across blood-brain barrier (BBB). However, molecular details endothelial response remain elusive. Objective: To map transcriptional changes resulting from lack contact at single-cell level correlate them with regional heterogeneities BBB function vascular phenotype. Methods Results: We reveal transcriptional, morphological, functional consequences absence for using combination methodologies, including RNA sequencing, tracer analyses, immunofluorescent detection protein expression pericyte-deficient adult Pdgfb ret/ret mice. find that without retain general BBB-specific gene profile, however, they acquire venous-shifted pattern become transformed regarding numerous growth factors regulatory proteins. Adult brains display ongoing angiogenic sprouting concomitant cell proliferation providing unique insights into tip transcriptome. also heterogeneous modes impairment, where hotspot sites arteriolar-shifted identity pinpoint putative regulators. By testing causal involvement some these reverse genetics, we uncover reinforcing angiopoietin 2 BBB. Conclusions: elucidating complexity cellular resolution, our study provides insight importance arterio-venous zonation, quiescence, limited set functions. The BBB-reinforcing ANGPT2 (angiopoietin 2) is paradoxical given its wider as TIE2 (TEK receptor tyrosine kinase) antagonist may suggest context-dependent brain.

Язык: Английский

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Pericyte Control of Blood Flow Across Microvascular Zones in the Central Nervous System

Annual Review of Physiology, Год журнала: 2021, Номер 84(1), С. 331 - 354

Опубликована: Окт. 21, 2021

The vast majority of the brain's vascular length is composed capillaries, where our understanding blood flow control remains incomplete. This review synthesizes current knowledge on across microvascular zones by addressing issues with nomenclature and drawing new developments from in vivo optical imaging single-cell transcriptomics. Recent studies have highlighted important distinctions mural cell morphology, gene expression, contractile dynamics, which can explain observed differences response to vasoactive mediators between arteriole, transitional, capillary zones. Smooth muscle cells arterioles ensheathing pericytes arteriole-capillary transitional zone large-scale, rapid changes flow. In contrast, downstream act slower smaller scales are involved establishing resting tone heterogeneity. Many unresolved remain, including that activate different pericyte types vivo, role pericyte-endothelial communication conducting signals capillaries arterioles, how neurological disease affects these mechanisms.

Язык: Английский

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Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Июль 11, 2023

Abstract Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large small vessels a key driver of age-related decline. Severe VCID includes post-stroke dementia, subcortical ischemic multi-infarct mixed dementia. While acknowledged as the second most common form after Alzheimer’s disease (AD) accounting for 20% cases, AD frequently coexist. In VCID, vessel (cSVD) often affects arterioles, capillaries, venules, where arteriolosclerosis amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent infarcts, lacunes presumed origin, enlarged perivascular space, microbleeds, brain atrophy neuroimaging hallmarks cSVD. The current primary approach to cSVD treatment control risk factors such hypertension, dyslipidemia, diabetes, smoking. However, causal therapeutic strategies have not been established partly due heterogeneous pathogenesis this review, we summarize pathophysiology discuss probable etiological pathways focusing on hypoperfusion/hypoxia, blood–brain barriers (BBB) dysregulation, fluid drainage disturbances, inflammation define potential diagnostic targets

Язык: Английский

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Pericytes in the disease spotlight

Trends in Cell Biology, Год журнала: 2023, Номер 34(1), С. 58 - 71

Опубликована: Июль 18, 2023

Molecular and functional pericyte studies at single-cell resolution are providing new insights into long-standing questions about heterogeneity.Pericytes not identified by a single marker but instead gene expression signatures that show substantial inter-organ differences.Pericytes orchestrate precede endothelial cell responses during angiogenesis.Pericyte degeneration dysfunction, triggered the onset of some diseases, contribute to progression those diseases in both vascular non-vascular contexts.The number with dysfunction continues expand, thereby anticipating promising future for pericyte-focused therapy. Pericytes classically defined as mural cells (see Glossary) envelop endothelium small caliber blood vessels, so-called capillaries. embedded within same basement membrane (ECs) interact closely them [1.Armulik A. et al.Pericytes: developmental, physiological, pathological perspectives, problems, promises.Dev. Cell. 2011; 21: 193-215Abstract Full Text PDF PubMed Scopus (1790) Google Scholar,2.Holm al.Microvascular organotypic heterogeneity plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract (63) Scholar]. By contrast, smooth muscle (vSMCs), other type, cover large arteries veins, physically separated from an intimal layer extracellular matrix (ECM). Of note, lymphatic capillaries lack pericytes under physiological conditions, although collecting vessels contain vSMCs [3.Petrova T.V. Koh G.Y. Biological functions vessels.Science. 2020; 369eaax4063Crossref (144) A fundamental function is regulate stabilization vessels. It therefore surprising loss were linked several including cancer cerebrovascular more than decade ago [4.Martin J.D. al.Normalizing tumor vessels: progress, opportunities, challenges.Annu. Rev. Physiol. 2019; 81: 505-534Crossref (242) Scholar,5.Lendahl U. al.Emerging links between neurodegenerative diseases-a special role pericytes.EMBO Rep. 20e48070Crossref (71) However, therapies have been poorly explored. Instead, most on vascular-directed therapeutic strategies ECs – central components build Emerging data are, however, changing perception mere supporting recruited final stage vessel formation essential elements early phases angiogenesis anticipate EC behavior. In addition, recent research revealing novel roles beyond their implications vasculature. Collectively, we believe these open exciting avenues approaches call broader understanding disease progression. We provide here global overview significant advances regarding our different pathobiological scenarios discuss field's current paradigms controversies. First, address associated responses. Second, evidence disease, cell-autonomous For comprehensive details biology, ontology, specific signaling pathways, refer reader importance, emerging concepts biology described following sections only studied one tissue. To avoid confusion generalizability properties, frame each considering relevant organ study. exhibit inter- intra-tissue molecular differences exert tissue-specific [2.Holm Their molecular, morphological, inextricably diverse developmental origins, modes recruitment, anatomical localization. example, nervous system (CNS) microvasculature firmly continuously invested around support barrier whereas liver pericytes, commonly referred hepatic stellate (HSCs), reside perisinusoidal space, loosely discontinuously ECs, hold unique vitamin storage capacity meet demands, distribution density variable among organs beds, CNS showing greatest pericyte-to-EC abundance. From standpoint there no can exclusively identify (Box 1), albeit emergence techniques shedding light markers functions. first atlas types brain adult mice RNA sequencing (scRNA-seq) revealed follow gradient transitional phenotypes. This occurs interface precapillary arterioles, capillaries, postcapillary venules, does continuum along arteriovenous axis (Figure 1 Box 1) [6.Vanlandewijck M. al.A zonation vasculature.Nature. 554: 475-480Crossref (876) Whether this phenotypes specifically restricted vasculature or also present beds remains be determined. Indeed, many 2 illustrates three top-ranked enriched per organ), which transporters contractile machinery [7.Muhl L. al.Single-cell analysis uncovers fibroblast criteria identification discrimination.Nat. Commun. 11: 3953Crossref (187) Another intriguing observation cross-organ Scholar,8.Muhl transcriptomic inventory murine cells.Dev. 2022; 57: 2426-2443Abstract Currently, inter-tissue behavior two main completely understood. may because greater cell-intrinsic plasticity adapt portfolio fulfill universal across tissues. contrast differences, transcription factors appears relatively conserved organs, suggesting subtypes epigenetic mechanisms Accordingly, DNA hypermethylation was recently found control alpha actin (αSMA) renal after ischemia [9.Chou Y.H. al.Methylation acute injury promotes chronic kidney disease.J. Clin. Invest. 130: 4845-4857Crossref (18) indicates methods such assay transposase-accessible chromatin (ATAC-seq) will instrumental further understand phenotypes.Box 1Unraveling identity pericytesThe challenging task. Despite ongoing efforts, consensus unambiguous identification. date all distinguish types, scRNA-seq now opportunities discern tissue specificity Scholar,71.Teuwen L.A. al.Tumor co-option probed analysis.Cell 2021; 35109253Abstract (35) Scholar,93.Baek S.H. al.Single reveals identities.Front Cardiovasc. Med. 9876591Crossref (9) The use transgenic reporter mouse models has label, trace, locate populations vivo. combination multiple lines often necessary properly discriminate perivascular Scholar, 7.Muhl 8.Muhl Mural highly plastic cells; phenotypic do Figure 1A,B text) transcriptional point view, distinct continuums cells: (i) capillary venous (SMCs), where gradually transition SMC phenotype, (ii) arterial SMCs pattern towards arteriole SMCs. resemblance venular Scholar], well classic led hypothesis transcriptionally morphologically similar Human recapitulate pattern, human evenly distributed over veins [50.Yang A.C. mediators Alzheimer's risk.Nature. 603: 885-892Crossref (117) Scholar,94.Garcia F.J. dissection 893-899Crossref (53) Unlike separation brain, discerned functionality marked solute transport (ECM) organization Unfortunately, ability predict presence limited, select few retain adequate specificity. zebrafish better alternative study genes [95.Shih al.Integrated identifies signature zebrafish.Development. 148dev200189Crossref (4) RGS5, NDUFA4L2, KNCJ8, HIGD1B, ABCC9, NOTCH3, PDGFRB currently species markers, detailed characterization when studying text).Figure 2Organotypic markers.Show full captionThis figure summarizes heart, lung, kidney, colon (upper row) (lower row). Pericyte chosen based stringent evaluation abundance, specificity, homogeneity utilizing information provided Scholar,50.Yang Scholar,82.Muhl al.The SARS-CoV-2 receptor ACE2 expressed COVID-19 research.Stem 17: 1089-1104Abstract (0) Scholar,84.Dobie R. transcriptomics mesenchyme fibrosis.Cell 29: 1832-1847Abstract (164) Scholar,85.Kuppe C. al.Decoding myofibroblast origins fibrosis.Nature. 589: 281-286Crossref (225) Scholar,95.Shih Scholar,100.Winkler E.A. normal malformed vasculature.Science. 375: eabi7377Crossref (5) 101.Travaglini K.J. lung sequencing.Nature. 587: 619-625Crossref (470) 102.Kinchen J. al.Structural remodeling colonic inflammatory bowel disease.Cell. 175: 372-386Abstract (313) Validation selected situ used second selection.View Large Image ViewerDownload Hi-res image Download (PPT) text). selection. Many documented [10.Potente al.Basic aspects angiogenesis.Cell. 146: 873-887Abstract (1978) historical view proposes mainly late stages Scholar,10.Potente taking advantage retina paradigmatic experimental model angiogenesis, concept challenged [11.Park D.Y. al.Plastic blood-retinal barrier.Nat. 2017; 8: 15296Crossref (175) 12.Figueiredo A.M. al.Phosphoinositide 3-kinase-regulated maturation governs remodeling.Circulation. 142: 688-704Crossref (25) 13.Orlich M.M. al.Mural SRF controls migration, patterning flow.Circ. Res. 131: 308-327Crossref 14.Dieguez-Hurtado al.Loss factor RBPJ induces disease-promoting properties pericytes.Nat. 10: 2817Crossref 15.Teichert al.Pericyte-expressed Tie2 maturation.Nat. 16106Crossref (174) 16.Eilken H.M. al.Pericytes VEGF-induced sprouting through VEGFR1.Nat. 1574Crossref (134) showed that, yet achieved maturity seen formed permissive cell-cycle progression, morphological adaptation, migration [12.Figueiredo Scholar,13.Orlich setting, growth precedes expansion it still unclear why. One possibility expanding rapidly, ensure production sufficient signals, coherent inhibition activation blocks proliferation Scholar] nuclear translocation FOXO1 master regulator quiescence [17.Kobialka P. Graupera Revisiting PI3-kinase signalling angiogenesis.Vasc. 1: H125-H134Crossref examined absent, become angiogenic able proliferate [18.Mae M.A. blood–brain response loss.Circ. 128: e46-e62Crossref require expand. Nonetheless, fair acknowledge shown reduced coverage leads increased [19.Dave J.M. al.Pericyte ALK5/TIMP3 contributes morphogenesis developing brain.Dev. 47: 388-389Abstract (8) Although discrepancies highlight pericyte–EC interactions complex, they explained animal genetic interfere pericytes. Importantly, behaviors mostly tissues belonging CNS. Hence, given high abundance CNS, possible substantially outnumber them. interesting immature remain close contact entirety Scholar,20.Crouch E.E. al.Ensembles promote prenatal brain.Cell. 185: 3753-3769Abstract (11) suggests communication relies paracrine juxtracrine signaling, explain why Pu

Язык: Английский

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Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms

Cancer Cell, Год журнала: 2024, Номер 42(3), С. 378 - 395.e10

Опубликована: Янв. 21, 2024

Brain metastasis (BrM) is a common malignancy, predominantly originating from lung, melanoma, and breast cancers. The vasculature key component of the BrM tumor microenvironment with critical roles in regulating metastatic seeding progression. However, heterogeneity major vascular components, namely endothelial mural cells, still poorly understood. We perform single-cell bulk RNA-sequencing sorted cell types detect multiple subtypes enriched specifically compared to non-tumor brain, including previously unrecognized immune regulatory subtypes. integrate human data mouse models, creating platform interrogate targets for treatment BrM. find that CD276 checkpoint molecule significantly upregulated vasculature, anti-CD276 blocking antibodies prolonged survival preclinical trials. This study provides important insights into complex interactions between cancer translational relevance designing therapeutic interventions.

Язык: Английский

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The Crucial Role of the Blood–Brain Barrier in Neurodegenerative Diseases: Mechanisms of Disruption and Therapeutic Implications

Journal of Clinical Medicine, Год журнала: 2025, Номер 14(2), С. 386 - 386

Опубликована: Янв. 9, 2025

The blood-brain barrier (BBB) is a crucial structure that maintains brain homeostasis by regulating the entry of molecules and cells from bloodstream into central nervous system (CNS). Neurodegenerative diseases such as Alzheimer's Parkinson's disease, well ischemic stroke, compromise integrity BBB. This leads to increased permeability infiltration harmful substances, thereby accelerating neurodegeneration. In this review, we explore mechanisms underlying BBB disruption, including oxidative stress, neuroinflammation, vascular dysfunction, loss tight junction integrity, in patients with neurodegenerative diseases. We discuss how breakdown contributes neurotoxicity, abnormal accumulation pathological proteins, all which exacerbate neuronal damage facilitate disease progression. Furthermore, potential therapeutic strategies aimed at preserving or restoring function, anti-inflammatory treatments, antioxidant therapies, approaches enhance integrity. Given role neurodegeneration, maintaining its represents promising approach slow prevent progression

Язык: Английский

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Multimodal transcriptomics reveal neurogenic aging trajectories and age-related regional inflammation in the dentate gyrus

Nature Neuroscience, Год журнала: 2025, Номер 28(2), С. 415 - 430

Опубликована: Янв. 6, 2025

Abstract The mammalian dentate gyrus (DG) is involved in certain forms of learning and memory, DG dysfunction has been implicated age-related diseases. Although neurogenic potential maintained throughout life the as neural stem cells (NSCs) continue to generate new neurons, neurogenesis decreases with advancing age, implications for cognitive decline disease. In this study, we used single-cell RNA sequencing characterize transcriptomic signatures their surrounding niche, identifying molecular changes associated aging from activation quiescent NSCs maturation fate-committed progeny. By integrating spatial transcriptomics data, identified regional invasion inflammatory into hippocampus age show here that early-onset neuroinflammation activity. Our data reveal lifelong dynamics niche provide a powerful resource understand alterations hippocampus.

Язык: Английский

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