title: Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer's disease-like mice.
abstract: Although central nervous system-resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer's disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell-based therapies for AD.
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prokop
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Miller
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Drost
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Handrick
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 Center for Tissue Regeneration, Repair, and Restoration, VA Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Vidhu
authors.initials: V
authors.lastname: Mathur
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 Center for Tissue Regeneration, Repair, and Restoration, VA Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Wegner
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 Center for Tissue Regeneration, Repair, and Restoration, VA Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany frank.heppner@charite.de.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000494:pharmacology; D008297:Male; D051379:Mice; D017628:Microglia / Q000502:physiology; D022423:Myeloid Cells / Q000502:physiology*; D014611:Vaccination
chemical_list: D016229:Amyloid beta-Peptides; D015774:Ganciclovir