Functional morphology of the blood–brain barrier in health and disease

Acta Neuropathologica, Journal Year: 2018, Volume and Issue: 135(3), P. 311 - 336

Published: Feb. 6, 2018

The adult quiescent blood–brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at same time. In past decade, there has been considerable progress understanding not only molecular pathways involved BBB development, also breakdown neurological diseases. Specifically, Wnt/β-catenin, retinoic acid sonic hedgehog moved into focus of research. Moreover, angiopoietin/Tie2 signalling that linked to angiogenic processes gained attention field. Blood vessels play an essential role initiation progression many diseases, including inflammation outside central nervous system (CNS). Therefore, potential influence CNS blood diseases associated alterations or neuroinflammation become major current research understand their contribution pathogenesis. remains obstacle pharmaceutical intervention CNS. complications may either be expressed inadequate therapeutic delivery like brain tumours, poor drug across ineffective bioavailability. this review, we initially describe cellular components contribute steady state healthy BBB. We then discuss ischaemic stroke, primary metastatic tumour, chronic Alzheimer's disease. Throughout highlight common mechanisms abnormalities among these particular dysfunction disease progression, emphasise unique aspects alteration certain such as tumours. review highlights novel strategies monitor function non-invasive imaging techniques focussing on well ways modulate permeability promote treatment conclusion, deep signals maintain fluctuations states will key elucidate identify targets for diagnostics modulation

Language: Английский

---

Claudin-5: gatekeeper of neurological function

Fluids and Barriers of the CNS, Journal Year: 2019, Volume and Issue: 16(1)

Published: Jan. 29, 2019

Tight junction proteins of the blood-brain barrier are vital for maintaining integrity endothelial cells lining brain blood vessels. The presence these protein complexes in space between creates a dynamic, highly regulated and restrictive microenvironment that is neural homeostasis. By limiting paracellular diffusion material brain, tight provide protective preventing passage unwanted potentially damaging material. Simultaneously, this hinders therapeutic effectiveness central nervous system acting drugs with over 95% small molecule therapeutics unable to bypass barrier. At barrier, claudin-5 most enriched its dysfunction has been implicated neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory multiple sclerosis well psychiatric including depression schizophrenia. regulating levels claudin-5, it possible abrogate disease symptoms many disorders. This review will give an overview role before focusing on regulation homeostatic pathological conditions. We also summarise strategies restore cerebral vessels by targeting complexes.

Language: Английский

---

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

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 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

Language: Английский

---

Markers for human brain pericytes and smooth muscle cells

Journal of Chemical Neuroanatomy, Journal Year: 2018, Volume and Issue: 92, P. 48 - 60

Published: June 7, 2018

Language: Английский

---

Identification of early pericyte loss and vascular amyloidosis in Alzheimer’s disease retina

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 139(5), P. 813 - 836

Published: Feb. 10, 2020

Abstract Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood–brain barrier breakdown described in Alzheimer’s disease (AD) that can predict cognitive decline yet have never been studied retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, histological examinations support existence vascular-structural abnormalities β-protein (Aβ) deposits retinas AD patients. However, cellular molecular mechanisms such pathology were not previously explored. Here, by modifying a method enzymatically clearing non-vascular tissue fluorescent immunolabeling isolated blood vessel network, we identified substantial pericyte together with significant Aβ deposition microvasculature pericytes AD. Evaluation postmortem from cohort 56 human donors revealed an early progressive decrease PDGFRβ mild impairment (MCI) compared to cognitively normal controls. Retinal significantly associated increased 40 42 burden. Decreased LRP-1 apoptosis retina also detected. Mapping levels pre-defined subregions indicated certain geometrical layers more susceptible pathology. Further, correlations between cerebral burden, angiopathy (CAA), clinical status. Overall, identification accompanying amyloidosis implies compromised blood–retinal integrity provides new targets for diagnosis therapy.

Language: Английский

---

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: Aug. 27, 2020

Schizophrenia is a disorder with heterogeneous etiology involving complex interplay between genetic and environmental risk factors. The immune system now known to play vital roles in nervous function pathology through regulating neuronal glial development, synaptic plasticity, behavior. In this regard, the positioned as common link seemingly diverse factors for schizophrenia. Synthesizing information about how immune-brain axis affected by multiple these might interact schizophrenia necessary better understand pathogenesis of disease. Such knowledge will aid development more translatable animal models that may lead effective therapeutic interventions. Here, we provide an overview modulate function. We also explore including exposure pollution, gut dysbiosis, maternal activation early-life stress, consequences are linked microglial dysfunction. propose morphological signaling deficits blood-brain barrier, observed some individuals schizophrenia, can act gateway peripheral central inflammation, thus affecting microglia their essential functions. Finally, describe response neuroinflammation impact on brain homeostasis, well pathophysiology.

Language: Английский

---

The CLDN5 gene at the blood-brain barrier in health and disease

Fluids and Barriers of the CNS, Journal Year: 2023, Volume and Issue: 20(1)

Published: March 28, 2023

Abstract The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions solutes. blood–brain barrier (BBB), composed brain microvascular associated pericytes end-feet astrocytes, a physical biological to maintain microenvironment. expression CLDN-5 tightly regulated BBB by other junctional proteins supports from astrocytes. most recent literature clearly shows compromised with decline increasing risks developing neuropsychiatric disorders, epilepsy, calcification dementia. purpose this review summarize known diseases function. In first part review, we highlight understanding how as well astrocytes cells. We detail some drugs can enhance these are being developed or currently use treat decline. then summarise mutagenesis-based studies have facilitated better physiological role protein at demonstrated functional consequences recently identified pathogenic missense mutation patients alternating hemiplegia childhood. This gain-of-function CLDN family all others representing loss-of-function mutations resulting mis-localization and/or attenuated Finally, reports about dosage-dependent effect on development neurological mice discuss what cellular for regulation human diseases.

Language: Английский

---

Pericytes in the disease spotlight

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 34(1), P. 58 - 71

Published: July 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

Language: Английский

---

The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium

Journal of Affective Disorders, Journal Year: 2023, Volume and Issue: 331, P. 300 - 312

Published: March 28, 2023

Language: Английский

---

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

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 378 - 395.e10

Published: Jan. 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.

Language: Английский

---