Complement in the Brain

doi:10.1016/J.MOLIMM.2011.04.003

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Complement in the Brain

Journal Article•DOI•

Complement in the Brain

Robert Veerhuis¹, Henrietta M. Nielsen², Andrea J. Tenner³•Institutions (3)

VU University Medical Center¹, Lund University², University of California, Irvine³

01 Aug 2011-Molecular Immunology (Elsevier Limited)-Vol. 48, Iss: 14, pp 1592-1603

TL;DR: Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation, which may give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention.

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About: This article is published in Molecular Immunology.The article was published on 2011-08-01 and is currently open access. It has received 354 citations till now. The article focuses on the topics: Complement receptor & Classical complement pathway.

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Journal Article•DOI•

Neuroinflammation in Alzheimer's disease

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Michael T. Heneka¹, Monica J. Carson², Joseph El Khoury³, Gary E. Landreth⁴, Frederic Brosseron, Douglas L. Feinstein⁵, Andreas H. Jacobs⁶, Tony Wyss-Coray⁷, Tony Wyss-Coray⁸, Javier Vitorica⁹, Richard M. Ransohoff¹⁰, Karl Herrup¹¹, Sally A. Frautschy¹², Bente Finsen¹³, Guy C. Brown¹⁴, Alexei Verkhratsky¹⁵, Alexei Verkhratsky¹⁶, Alexei Verkhratsky¹⁷, Koji Yamanaka¹⁸, Jari Koistinaho¹⁹, Eicke Latz²⁰, Eicke Latz²¹, Annett Halle²², Gabor C. Petzold¹, Terrence Town²³, Dave Morgan²⁴, Mari L. Shinohara²⁵, V. Hugh Perry²⁶, Clive Holmes²⁷, Clive Holmes²⁸, Nicolas G. Bazan²⁹, David J. Brooks³⁰, Stéphane Hunot³¹, Bertrand Joseph³², Nikolaus Deigendesch³³, Olga Garaschuk³⁴, Erik Boddeke³⁵, Charles A. Dinarello³⁶, John C.S. Breitner³⁷, Greg M. Cole¹², Douglas T. Golenbock²¹, Markus P. Kummer¹ - Show less +38 more•Institutions (37)

University Hospital Bonn¹, University of California, Riverside², Harvard University³, Case Western Reserve University⁴, University of Illinois at Chicago⁵, European Institute⁶, Stanford University⁷, VA Palo Alto Healthcare System⁸, Spanish National Research Council⁹, Cleveland Clinic Lerner Research Institute¹⁰, Hong Kong University of Science and Technology¹¹, University of California, Los Angeles¹², University of Southern Denmark¹³, University of Cambridge¹⁴, University of the Basque Country¹⁵, Ikerbasque¹⁶, University of Manchester¹⁷, RIKEN Brain Science Institute¹⁸, University of Eastern Finland¹⁹, University of Bonn²⁰, University of Massachusetts Medical School²¹, Center of Advanced European Studies and Research²², University of Southern California²³, University of South Florida²⁴, Duke University²⁵, Southampton General Hospital²⁶, University of Southampton²⁷, Moorgreen Hospital²⁸, Louisiana State University²⁹, Imperial College London³⁰, Centre national de la recherche scientifique³¹, Karolinska Institutet³², Max Planck Society³³, University of Tübingen³⁴, University of Groningen³⁵, University of Colorado Denver³⁶, Douglas Mental Health University Institute³⁷

01 Apr 2015-Lancet Neurology

TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.

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Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

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3,947 citations

Journal Article•DOI•

The complement system: an unexpected role in synaptic pruning during development and disease.

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Alexander Stephan¹, Ben A. Barres¹, Beth Stevens²•Institutions (2)

Stanford University¹, Harvard University²

20 Jun 2012-Annual Review of Neuroscience

TL;DR: Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression.

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Abstract: An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complementmediated synapse elimination potentially driving disease progression.

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864 citations

Cites background from "Complement in the Brain"

...We know that complement proteins are upregulated in neural cells following brain injury (reviewed in Veerhuis et al. 2011), but comparatively little is known about the normal function of complement proteins in the healthy brain....
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...In the CNS, complement proteins are locally synthesized by resident neurons and glial cells; however, microglia and astrocytes are the major producers of complement in the healthy and diseased CNS (Lampert-Etchells et al. 1993, Barnum 1995, Woodruff et al. 2010, Veerhuis et al. 2011)....
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...Although the blood brain barrier normally protects the brain from plasma-derived complement and infiltrating immune cells, many complement components can be locally produced in the brain, most often in response to injury or inflammatory signals (Zamanian et al. 2012, Veerhuis et al. 2011)....
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...…appreciated as a rapid and local immune surveillance system in the brain; however, new research has ascribed many new functions of complement in the brain that extend far beyond host defense and inflammatory processes (reviewed in Ricklin et al. 2010, Rutkowski et al. 2010b, Veerhuis et al. 2011)....
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...…are profoundly upregulated in Alzheimer’s disease (AD), glaucoma, and other brain diseases (reviewed in Alexander et al. 2008, Rosen & Stevens 2010, Veerhuis et al. 2011) and are localized to synapses prior to signs of neuronal loss in animal models of neurodegenerative disease (Stevens et al.…...
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Journal Article•DOI•

Epilepsy and brain inflammation.

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Annamaria Vezzani¹, Eleonora Aronica, Andrey Mazarati², Quentin J. Pittman³•Institutions (3)

Mario Negri Institute for Pharmacological Research¹, University of California, Los Angeles², University of Calgary³

01 Jun 2013-Experimental Neurology

TL;DR: The clinical observations in drug-resistant human epilepsies and the experimental findings in adult and immature rodents linking brain inflammation to the epileptic process in a causal and reciprocal manner are reported.

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490 citations

Journal Article•DOI•

The blood–brain barrier in health and disease

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Richard Daneman¹•Institutions (1)

University of California, San Francisco¹

01 Nov 2012-Annals of Neurology

TL;DR: This review discusses the cellular and molecular composition of the blood–brain barrier and how the development and function of the BBB is regulated by interactions with the CNS microenvironment.

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Abstract: The blood-brain barrier (BBB) is a term used to describe a series of properties possessed by the vasculature of the central nervous system (CNS) that tightly regulate the movement of ions, molecules, and cells between the blood and the CNS. This barrier is crucial to provide the appropriate environment to allow for proper neural function, as well as protect the CNS from injury and disease. In this review, I discuss the cellular and molecular composition of the BBB and how the development and function of the BBB is regulated by interactions with the CNS microenvironment. I further discuss what is known about BBB dysfunction during CNS injury and disease, as well as methodology used to deliver drugs across the BBB to the CNS.

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464 citations

Cites background from "Complement in the Brain"

...Complement deposition has been identified in different neurodegenerative disorders and can induce antibody-independent neuronal cell lysis as well as activation of astrocytes and the inflammatory response.(289,290)...
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Journal Article•DOI•

Phagocytosis of Microglia in the Central Nervous System Diseases

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Ruying Fu¹, Qingyu Shen¹, Pengfei Xu¹, Jin Jun Luo², Yamei Tang², Yamei Tang¹ - Show less +2 more•Institutions (2)

Sun Yat-sen University¹, Temple University²

07 Jan 2014-Molecular Neurobiology

TL;DR: This review focuses on phagocytic phenotype of microglia in neurological diseases such as Alzheimer's disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury, ischemic and other brain diseases.

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Abstract: Microglia, the resident macrophages of the central nervous system, rapidly activate in nearly all kinds of neurological diseases. These activated microglia become highly motile, secreting inflammatory cytokines, migrating to the lesion area, and phagocytosing cell debris or damaged neurons. During the past decades, the secretory property and chemotaxis of microglia have been well-studied, while relatively less attention has been paid to microglial phagocytosis. So far there is no obvious concordance with whether it is beneficial or detrimental in tissue repair. This review focuses on phagocytic phenotype of microglia in neurological diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury, ischemic and other brain diseases. Microglial morphological characteristics, involved receptors and signaling pathways, distribution variation along with time and space changes, and environmental factors that affecting phagocytic function in each disease are reviewed. Moreover, a comparison of contributions between macrophages from peripheral circulation and the resident microglia to these pathogenic processes will also be discussed.

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436 citations

Cites background from "Complement in the Brain"

...Besides these two types, some receptors including Fc receptors, complement receptors [18], scavenger receptors (SR), pyrimidinergic receptor P2Y, G-protein coupled, 6 (P2RY6), macrophage antigen complex 2 (MAC-2), mannose receptor [19], and low-density lipoprotein receptor-related protein (LRP) receptor also participate in microglial clearance of misfolded, apoptotic cells and dead neurons in both acute and chronic brain injury [20]....
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References

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Open Access

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Journal Article•DOI•

The chemokine system in diverse forms of macrophage activation and polarization.

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Alberto Mantovani¹, Alberto Mantovani², Antonio Sica¹, Silvano Sozzani¹, Silvano Sozzani³, Paola Allavena¹, Annunciata Vecchi¹, Massimo Locati² - Show less +4 more•Institutions (3)

Mario Negri Institute for Pharmacological Research¹, University of Milan², University of Brescia³

01 Dec 2004-Trends in Immunology

TL;DR: Recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.

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5,568 citations

Journal Article•DOI•

Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo

[...]

Axel Nimmerjahn¹, Frank Kirchhoff¹, Fritjof Helmchen¹•Institutions (1)

Max Planck Society¹

27 May 2005-Science

TL;DR: Using in vivo two-photon imaging in neocortex, it is found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions.

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Abstract: Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.

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4,458 citations

"Complement in the Brain" refers background in this paper

...Microglia, the macrophages of the brain, are scattered throughout the brain tissue at a density of about 6x10 6 cells per mm 3 and, when in a “resting” state are highly dynamic and estimated to completely scan the brain parenchyma once every few hours (Nimmerjahn et al., 2005)....
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Journal Article•DOI•

Structure and function of the blood–brain barrier

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N. Joan Abbott¹, Adjanie Patabendige¹, Diana E. M. Dolman¹, Siti R. Yusof¹, David J. Begley¹ - Show less +1 more•Institutions (1)

King's College London¹

01 Jan 2010-Neurobiology of Disease

TL;DR: The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms are described.

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3,783 citations

"Complement in the Brain" refers background in this paper

...Together these brain barriers efficiently prevent infiltration of circulating immune cells, such as B- and T lymphocytes, and minimize influx of plasma proteins as well as neuroexcitatory and neurotoxic substances from the blood (reviewed in (Abbott et al., 2010))....
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...Role of toll- like receptor signalling in Abeta uptake and clearance....
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...Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line....
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...C4b-binding protein in Alzheimer's disease: binding to Abeta1-42 and to dead cells....
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...Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line....
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Journal Article•DOI•

Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.

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Claudia F. Lucchinetti¹, Wolfgang Brück², Joseph E. Parisi¹, Bernd W. Scheithauer¹, Moses Rodriguez¹, Hans Lassmann³ - Show less +2 more•Institutions (3)

Mayo Clinic¹, University of Göttingen², University of Vienna³

01 Jun 2000-Annals of Neurology

TL;DR: At a given time point of the disease, the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient, suggesting that MS may be a disease with heterogeneous pathogenetic mechanisms.

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Abstract: Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell‐mediated or T-cell plus antibody‐mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease—as reflected in autopsy cases—the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.

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3,162 citations

"Complement in the Brain" refers result in this paper

...…et al., 2009;Storch et al., 1998) , all of which is consistent with the possible involvement of C in myelin degradation in MS. Based on observed differences in occurrence of C deposition between cases, a classification with 4 pathological subtypes of MS was proposed (Lucchinetti et al., 2000)....
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Journal Article•DOI•

Complement: a key system for immune surveillance and homeostasis

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Daniel Ricklin¹, George Hajishengallis², Kun Yang¹, John D. Lambris¹•Institutions (2)

University of Pennsylvania¹, University of Louisville²

01 Sep 2010-Nature Immunology

TL;DR: An updated view of the function, structure and dynamics of the complement network is described, its interconnection with immunity at large and with other endogenous pathways is highlighted, and its multiple roles in homeostasis and disease are illustrated.

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Abstract: Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

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2,986 citations

"Complement in the Brain" refers background in this paper

...Complement proteins were found to promote proliferation and regeneration in various tissues (reviewed in (Ricklin et al., 2010)) and may exert similar functions in the CNS, as neuronal stem cells differentiate and migrate in response to C. C3a-C3aR interactions were found to be a positive regulator…...
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...Complement (C) is a major component of innate immunity, recognizing danger, as well as discriminating self from non-self (Ricklin et al., 2010)....
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