Alon Monsonego

Ben-Gurion University of the Negev, Be'er Sheva`, Southern District, Israel

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Publications (72)299.75 Total impact

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    [Show abstract] [Hide abstract] ABSTRACT: TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-β signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6 -: treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-β1 -: induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte -: neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death. Copyright © 2015 by The American Association of Immunologists, Inc.
    Full-text · Article · Oct 2014 · Journal of Neuroimmunology
  • No preview · Conference Paper · Aug 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Fig. S1 IbaI-stained microglial process complexity deteriorates with aging.
    Preview · Dataset · Mar 2014
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    Preview · Dataset · Mar 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Table S2 Morphological analysis of IbaI+ cells close and distant from Aβ plaques in APPsw, Ind.
    Preview · Dataset · Mar 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Fig. S2 Microglia accumulation at sites of Aβ deposition in mouse models of AD.
    Preview · Dataset · Mar 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Table S1 Microglial process complexity deteriorates with aging.
    Preview · Dataset · Mar 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Microglia integrate within the neural tissue with a distinct ramified morphology through which they scan the surrounding neuronal network. Here, we used a digital tool for the quantitative morphometric characterization of fine cortical microglial structures in mice, and the changes they undergo with aging and in Alzheimer's-like disease. We show that, compared with microglia in young mice, microglia in old mice are less ramified and possess fewer branches and fine processes along with a slightly increased proinflammatory cytokine expression. A similar microglial pathology appeared 6–12 months earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to enhanced cognitive decline.
    Preview · Article · Mar 2014 · Aging cell
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    [Show abstract] [Hide abstract] ABSTRACT: Although CD4 T cells reside within the cerebrospinal fluid, it is yet unclear whether and how they enter the brain parenchyma and migrate to target specific Ags. We examined the ability of Th1, Th2, and Th17 CD4 T cells injected intracerebroventricularly to migrate from the lateral ventricles into the brain parenchyma in mice. We show that primarily Th1 cells cross the ependymal layer of the ventricle and migrate within the brain parenchyma by stimulating an IFN-γ-dependent dialogue with neural cells, which maintains the effector function of the T cells. When injected into a mouse model of Alzheimer's disease, amyloid-β (Aβ)-specific Th1 cells target Aβ plaques, increase Aβ uptake, and promote neurogenesis with no evidence of pathogenic autoimmunity or neuronal loss. Overall, we provide a mechanistic insight to the migration of cerebrospinal fluid CD4 T cells into the brain parenchyma and highlight implications on brain immunity and repair.
    Full-text · Article · Dec 2013 · The Journal of Immunology
  • M. Fassler · I Weissberg · N. Levi · A. Monsonego · A. Friedman · R. Taube
    No preview · Conference Paper · Nov 2013
  • R. Baron · A. Namirovsky · A. Monsonego
    No preview · Conference Paper · Nov 2013
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    [Show abstract] [Hide abstract] ABSTRACT: The ability to visualize and genetically manipulate specific cell populations of the central nervous system (CNS) is fundamental to a better understanding of brain functions at the cellular and molecular levels. Tools to selectively target cells of the CNS include molecular genetics, imaging, and use of transgenic animals. However, these approaches are technically challenging, time consuming, and difficult to control. Viral-mediated targeting of cells in the CNS can be highly beneficial for studying and treating neurodegenerative diseases. Yet, despite specific marking of numerous cell types in the CNS, in vivo selective targeting of astrocytes has not been optimized. In this study, preferential targeting of astrocytes in the CNS was demonstrated using engineered lentiviruses that were pseudotyped with a modified Sindbis envelope and displayed anti-GLAST IgG on their surfaces as an attachment moiety. Viral tropism for astrocytes was initially verified in vitro in primary mixed glia cultures. When injected into the brains of mice, lentiviruses that displayed GLAST IgG on their surface, exhibited preferential astrocyte targeting, compared to pseudotyped lentiviruses that did not incorporate any IgG or that expressed a control isotype IgG. Overall, this approach is highly flexible and can be exploited to selectively target astrocytes or other cell types of the CNS. As such, it can open a window to visualize and genetically manipulate astrocytes or other cells of the CNS as means of research and treatment.
    Full-text · Article · Oct 2013 · PLoS ONE
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    Alon Monsonego · Anna Nemirovsky · Idan Harpaz
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid-beta (Aβ) peptides and neurofibrillary tangles in the brain associated with glial activation and synpatotoxicity. In addition, AD involves peripheral and brain-endogenous inflammatory processes that appear to enhance disease progression. More than a decade ago a new therapeutic paradigm has emerged for AD, namely the activation of the adaptive immune system directly against the self-peptide Aβ, aiming at lowering its accumulation in the brain. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach took several turns, from initially active to passive and then back to modified active vaccines. As the two first approaches to date failed to show sufficient efficacy, the latter is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Aβ in human and mice and discusses past, present and future Aβ-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T-cell responsiveness evident in the disease. © 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.
    Full-text · Article · Mar 2013 · Immunology
  • [Show abstract] [Hide abstract] ABSTRACT: Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in urine CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL6 mice. Under baseline (non-stressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift towards proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4(+) CD25(+) Treg cells. This demonstrates that whereas C57BL6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.
    No preview · Article · Mar 2013 · European Journal of Immunology
  • I Harpaz · A. Monsonego · C. Hagit
    No preview · Conference Paper · Nov 2012
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    [Show abstract] [Hide abstract] ABSTRACT: Proper function of the neurovasculature is required for optimal brain function and preventing neuroinflammation and neurodegeneration. Within this review, we discuss alterations of the function of the blood–brain barrier in neurologic disorders such as multiple sclerosis, epilepsy, and Alzheimer’s disease and address potential underlying mechanisms.
    Full-text · Article · Nov 2012 · Epilepsia
  • [Show abstract] [Hide abstract] ABSTRACT: Microglia are myeloid-derived cells that colonize the central nervous system (CNS) at early stages of development and constitute up to 20% of the glial populations throughout life. While extensive progress has been recently made in identifying the cellular origin of microglia, the mechanism whereby the cells acquire the unique ramified and quiescent phenotype within the CNS milieu remains unknown. Here, we show that upon co-culturing of either CD117(+) /Lin(-) hematopoietic progenitors or CD11c(+) bone marrow derived cells with organotypic hippocampal slices or primary glia, the cells acquire a ramified morphology concomitant with reduced levels of CD86, MHCII, and CD11c and up-regulation of the microglial cell-surface proteins CX(3) CR1 and Iba-1. We further demonstrate that the transforming growth factor beta (TGF-β) signaling pathway via SMAD2/3 phosphorylation is essential for both primary microglia and myeloid-derived cells in order to acquire their quiescent phenotype. Our study suggests that the abundant expression of TGF-β within the CNS during development and various inflammatory processes plays a key role in promoting the quiescent phenotype of microglia and may thus serve as a target for therapeutic strategies aimed at modulating the function of microglia in neurodegenerative diseases such as Alzheimer's and prion.
    No preview · Article · Jul 2012 · Glia
  • [Show abstract] [Hide abstract] ABSTRACT: Aβ vaccination has been shown to induce remarkable clearance of brain amyloid plaques in mouse models of Alzheimer's disease (AD). However, the extent to which antibody-mediated Aβ clearance is affected by predominant formation of Aβ42 over Aβ40 is unclear. Here we demonstrate for the first time that in a mouse model carrying the human APP mutations KM670/671NL and the human PS1 mutation P166L, Aβ vaccination does not result in plaque clearance. This was in spite of the strong T- and B-cell immune responses evoked under the DR1501 genetic background and the activation of microglia at sites of Aβ plaques. Our findings suggest the existence of antibody-resistant forms of Aβ deposits in the brain consisting of primarily Aβ42, and shed light on the mechanisms of antibody-dependent amyloid clearance as well as novel therapeutic strategies for AD.
    No preview · Article · Apr 2012 · Journal of neuroimmunology
  • Yair Fisher · Anna Nemirovsky · Rona Baron · Alon Monsonego
    [Show abstract] [Hide abstract] ABSTRACT: Amyloid-β (Aβ) accumulation in the brain is one of the hallmarks of Alzheimer's disease (AD). T-cell entry into vascular and parenchymal brain areas loaded with Aβ has been observed with both beneficial as well as detrimental effects. Using a new AD mouse model, we studied the molecular mechanisms allowing CD4 T cells to specifically target Aβ-loaded brain areas. We observed that following Aβ immunization, CD11c+ dendritic cells (DCs) and CD4 T cells occurred primarily in the perivascular and leptomeningial spaces of cerebral vessels deposited with Aβ. CD11c+ cells expressed high levels of the DC maturation markers DEC-205, MHC class II and CD86. Notably, the majority of cerebral blood vessels were found adjacent to Aβ plaques, expressing high levels of the ICAM-1 and VCAM-1 adhesion molecules. We propose that the drainage of Aβ to the leptomeningeal and perivascular spaces and its deposition there provide the antigenic source for DCs to stimulate Aβ-specific T cells on their way to target amyloid plaques within the brain tissue.
    No preview · Article · Jul 2011 · Journal of Alzheimer's disease: JAD
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    Anna Nemirovsky · Yair Fisher · Rona Baron · Irun R Cohen · Alon Monsonego
    [Show abstract] [Hide abstract] ABSTRACT: Active vaccination with amyloid beta peptide (Aβ) to induce beneficial antibodies was found to be effective in mouse models of Alzheimer's disease (AD), but human vaccination trials led to adverse effects, apparently caused by exuberant T-cell reactivity. Here, we sought to develop a safer active vaccine for AD with reduced T-cell activation. We treated a mouse model of AD carrying the HLA-DR DRB1*1501 allele, with the Aβ B-cell epitope (Aβ 1-15) conjugated to the self-HSP60 peptide p458. Immunization with the conjugate led to the induction of Aβ-specific antibodies associated with a significant reduction of cerebral amyloid burden and of the accompanying inflammatory response in the brain; only a mild T-cell response specific to the HSP peptide but not to the Aβ peptide was found. This type of vaccination, evoking a gradual increase in antibody titers accompanied by a mild T-cell response is likely due to the unique adjuvant and T-cell stimulating properties of the self-HSP peptide used in the conjugate and might provide a safer approach to effective AD vaccination.
    Full-text · Article · May 2011 · Vaccine

Publication Stats

2k Citations
299.75 Total Impact Points


  • 2006-2012
    • Ben-Gurion University of the Negev
      • • Shraga Segal Department of Microbiology and Immunology
      • • Faculty of Health Sciences
      Be'er Sheva`, Southern District, Israel
  • 2009
    • National Research Council Canada
      Ottawa, Ontario, Canada
  • 2003-2006
    • Brigham and Women's Hospital
      • Center for Neurologic Diseases
      Boston, Massachusetts, United States
  • 2001
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1999
    • Weizmann Institute of Science
      • Department of Immunology