[en] Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APP(swe/PS1), APP(swe), and APP23 mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to β-amyloid (Aβ) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and Aβ load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired β-amyloid clearance and amplified vascular Aβ deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD.
Disciplines :
Neurologie
Auteur, co-auteur :
Mildner, Alexander; Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany
Schlevogt, Bernhard; Department of Neuropathology, Universitätsmedizin Göttingen, D-37099 Göttingen, Germany
Kierdorf, Katrin; Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany ; Faculty of Biology, University of Freiburg, D-79104 Freiburg, Germany
Böttcher, Chotima; Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, BCRT and NeuroCure, Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany
Erny, Daniel; Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany
Kummer, Markus P; Department of Neurology, Rheinische Friedrich-Wilhelms-Universität, D-53127 Bonn, Germany
Quinn, Michael; Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, BCRT and NeuroCure, Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany
Brück, Wolfgang; Department of Neuropathology, Universitätsmedizin Göttingen, D-37099 Göttingen, Germany
Bechmann, Ingo; Institute of Anatomy, University of Leipzig, D-04103 Leipzig, Germany
HENEKA, Michael ; Department of Neurology, Rheinische Friedrich-Wilhelms-Universität, D-53127 Bonn, Germany
Priller, Josef; Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, BCRT and NeuroCure, Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany
Prinz, Marco; Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease.
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