Cargando…

Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice

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-cl...

Descripción completa

Detalles Bibliográficos
Autores principales: Prokop, Stefan, Miller, Kelly R., Drost, Natalia, Handrick, Susann, Mathur, Vidhu, Luo, Jian, Wegner, Anja, Wyss-Coray, Tony, Heppner, Frank L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612091/
https://www.ncbi.nlm.nih.gov/pubmed/26458768
http://dx.doi.org/10.1084/jem.20150479
_version_ 1782396130745647104
author Prokop, Stefan
Miller, Kelly R.
Drost, Natalia
Handrick, Susann
Mathur, Vidhu
Luo, Jian
Wegner, Anja
Wyss-Coray, Tony
Heppner, Frank L.
author_facet Prokop, Stefan
Miller, Kelly R.
Drost, Natalia
Handrick, Susann
Mathur, Vidhu
Luo, Jian
Wegner, Anja
Wyss-Coray, Tony
Heppner, Frank L.
author_sort Prokop, Stefan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4612091
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-46120912016-04-19 Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice Prokop, Stefan Miller, Kelly R. Drost, Natalia Handrick, Susann Mathur, Vidhu Luo, Jian Wegner, Anja Wyss-Coray, Tony Heppner, Frank L. J Exp Med Brief Definitive Report 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. The Rockefeller University Press 2015-10-19 /pmc/articles/PMC4612091/ /pubmed/26458768 http://dx.doi.org/10.1084/jem.20150479 Text en © 2015 Prokop et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Prokop, Stefan
Miller, Kelly R.
Drost, Natalia
Handrick, Susann
Mathur, Vidhu
Luo, Jian
Wegner, Anja
Wyss-Coray, Tony
Heppner, Frank L.
Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
title Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
title_full Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
title_fullStr Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
title_full_unstemmed Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
title_short Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
title_sort impact of peripheral myeloid cells on amyloid-β pathology in alzheimer’s disease–like mice
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612091/
https://www.ncbi.nlm.nih.gov/pubmed/26458768
http://dx.doi.org/10.1084/jem.20150479
work_keys_str_mv AT prokopstefan impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT millerkellyr impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT drostnatalia impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT handricksusann impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT mathurvidhu impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT luojian impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT wegneranja impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT wysscoraytony impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice
AT heppnerfrankl impactofperipheralmyeloidcellsonamyloidbpathologyinalzheimersdiseaselikemice