title: Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes.
abstract: BACKGROUND
  Alzheimer's disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD.
  
  
  RESULTS
  Chronic infection with T. gondii was associated with reduced Aβ and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2(hi) Ly6C(hi) monocytes, CCR2(+) Ly6C(int), and CCR2(+) Ly6C(low) mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Aβ ex vivo. The F4/80(+) Ly6C(low) macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2(+) Ly6C(hi) monocytes resulted in an increased amount of Aβ in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits β1i/LMP2, β2i/MECL-1, and β5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Aβ degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Aβ clearance.
  
  
  CONCLUSIONS
  Our results indicate that chronic Toxoplasma infection ameliorates β-amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6C(hi) monocytes and by enhancement of phagocytosis and degradation of soluble Aβ. Our findings provide evidence for a modulatory role of inflammation-induced Aβ phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD.
authors.affiliation: Institute for Medical Microbiology and Hospital Hygiene, University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Möhle
authors.affiliation: Institute for Molecular and Clinical Immunology, University of Magdeburg, Magdeburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Israel
authors.affiliation: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway.|German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.|Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Paarmann
authors.affiliation: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway.
authors.forename: Markus
authors.initials: M
authors.lastname: Krohn
authors.affiliation: Department of Translational Inflammation Research, Institute of Experimental Internal Medicine, University of Magdeburg, Magdeburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pietkiewicz
authors.affiliation: Institute for Molecular and Clinical Immunology, University of Magdeburg, Magdeburg, Germany.|Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Müller
authors.affiliation: Department of Translational Inflammation Research, Institute of Experimental Internal Medicine, University of Magdeburg, Magdeburg, Germany.
authors.forename: Inna N
authors.initials: IN
authors.lastname: Lavrik
authors.affiliation: Genetic Engineering and Biotechnology News, New York, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Buguliskis
authors.affiliation: Center for Behavioral Brain Sciences (CBBS), University of Magdeburg, Magdeburg, Germany.|Department of Behavioral Neurology, Leibniz Institute for Neurobiology, Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, Campus Mitte, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Björn H
authors.initials: BH
authors.lastname: Schott
authors.affiliation: Institute for Medical Microbiology and Hospital Hygiene, University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany.|Center for Behavioral Brain Sciences (CBBS), University of Magdeburg, Magdeburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
authors.affiliation: Center for Behavioral Brain Sciences (CBBS), University of Magdeburg, Magdeburg, Germany.|Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.|Medical Faculty, University of Magdeburg, Magdeburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.affiliation: Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Montag
authors.affiliation: Institute for Molecular and Clinical Immunology, University of Magdeburg, Magdeburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
authors.affiliation: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway.|University of Lübeck (UzL), LIED, Lübeck, Germany.|Leibniz Institute of Plant Biochemistry (IPB), Halle, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.affiliation: Institute for Medical Microbiology and Hospital Hygiene, University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. ildikodunay@gmail.com.|Center for Behavioral Brain Sciences (CBBS), University of Magdeburg, Magdeburg, Germany. ildikodunay@gmail.com.
authors.forename: Ildiko Rita
authors.identifier: http://orcid.org/0000-0002-9900-8605
authors.initials: IR
authors.lastname: Dunay
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001921:Brain / Q000469:parasitology / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D014123:Toxoplasmosis / Q000378:metabolism* / Q000473:pathology*
chemical_list: C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D000906:Antibodies; D015703:Antigens, CD; D000950:Antigens, Ly; D002135:Calcium-Binding Proteins; C515335:Ccr2 protein, mouse; D005904:Glial Fibrillary Acidic Protein; C494192:Ly-6C antigen, mouse; D008840:Microfilament Proteins; D054390:Receptors, CCR2
keywords: Alzheimer’s disease; Aβ clearance; Chronic infection; Ly6Chi monocytes; Toxoplasma gondii