title: Interleukin-1β mediated amyloid plaque clearance is independent of CCR2 signaling in the APP/PS1 mouse model of Alzheimer's disease.
abstract: Neuroinflammation is a key component of Alzheimer's disease (AD) pathogenesis. Particularly, the proinflammatory cytokine interleukin-1 beta (IL-1β) is upregulated in human AD and believed to promote amyloid plaque deposition. However, studies from our laboratory have shown that chronic IL-1β overexpression in the APPswe/PSEN1dE9 (APP/PS1) mouse model of AD ameliorates amyloid pathology, increases plaque-associated microglia, and induces recruitment of peripheral immune cells to the brain parenchyma. To investigate the contribution of CCR2 signaling in IL-1β-mediated amyloid plaque clearance, seven month-old APP/PS1/CCR2(-/-) mice were intrahippocampally transduced with a recombinant adeno-associated virus serotype 2 containing the cleaved form of human IL-1β (rAAV2-IL-1β). Four weeks after rAAV2-IL-1β transduction, we found significant reductions in 6E10 and Congo red staining of amyloid plaques that was confirmed by decreased levels of insoluble Aβ1-42 and Aβ1-40 in the inflamed hippocampus. Bone marrow chimeric studies confirmed the presence of infiltrating immune cells following IL-1β overexpression and revealed that dramatic reduction of CCR2(+) peripheral mononuclear cell recruitment to the inflamed hippocampus did not prevent the ability of IL-1β to induce amyloid plaque clearance. These results suggest that infiltrating CCR2(+) monocytes do not contribute to IL-1β-mediated amyloid plaque clearance.
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Fátima
authors.initials: F
authors.lastname: Rivera-Escalera
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Matousek
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Simantini
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Olschowka
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: kerry_obanion@urmc.rochester.edu.
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000276:immunology* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018183:Transplantation Chimera
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C515335:Ccr2 protein, mouse; C508585:IL1B protein, human; D053583:Interleukin-1beta; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D054390:Receptors, CCR2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Bone marrow derived; CCL2; CCR2; Interleukin-1β; Monocytes; Neuroinflammation