title: Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schlevogt
authors.forename: Katrin
authors.initials: K
authors.lastname: Kierdorf
authors.forename: Chotima
authors.initials: C
authors.lastname: Böttcher
authors.forename: Daniel
authors.initials: D
authors.lastname: Erny
authors.forename: Markus P
authors.initials: MP
authors.lastname: Kummer
authors.forename: Michael
authors.initials: M
authors.lastname: Quinn
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D039481:CD11b Antigen / Q000378:metabolism; D016923:Cell Death / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002490:Central Nervous System / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D042282:Microdissection / Q000379:methods; D017628:Microglia / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000145:classification* / Q000502:physiology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000378:metabolism; D014916:Whole-Body Irradiation / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; D019394:Ki-67 Antigen; D054390:Receptors, CCR2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins