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. 2015 Oct 19;212(11):1811-8.
doi: 10.1084/jem.20150479. Epub 2015 Oct 12.

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

Stefan Prokop  1 , Kelly R Miller  1 , Natalia Drost  1 , Susann Handrick  1 , Vidhu Mathur  2 , Jian Luo  2 , Anja Wegner  1 , Tony Wyss-Coray  2 , Frank L Heppner  3
Affiliations

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

Stefan Prokop et al. J Exp Med. .

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.

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Figures

Figure 1.
Figure 1.
Peripheral origin of repopulating myeloid cells in nonchimeric microglia-depleted parabiotic mice. TK and Act.GFP mice were surgically connected to establish a joined circulatory system. Upon establishment of blood chimerism in both partners (2 wk), icv GCV was administered to the TK partners for 10 d to deplete microglia. Mice were sacrificed 24 d after starting GCV treatment. (a and b) Representative images of GFP-positive cells (middle columns) in microglia-depleted (GCV-treated) TK mice (bottom rows), WT controls (top rows), or non-microglia–depleted aCSF-treated TK controls (middle rows). Shown are cortical (a) or hippocampal (b) brain regions stained for Iba1 (left columns) or GFP (middle columns), as well as merged images (right columns). Bars, 200 µm. (c) Flow cytometric analysis of GFP+ cells in blood of parabiotic pairs. (d and e) Stereological quantification of Iba1-positive cells (d; *, P = 0.03; n = 5 per group) and GFP-positive cells (e; *, P = 0.02; n = 5 per group) in brains of mice described in a–c. All data are displayed as mean ± SEM.
Figure 2.
Figure 2.
Peripheral myeloid cells do not affect Aβ pathology in microglia-depleted APPPS1;TK+/− mice. (a) Representative images of Iba1 immunohistochemistry (blue) in peripheral myeloid cell–repopulated APPPS1;TK+/− mice (bottom) and similarly GCV-treated APPPS1;TK−/− control mice (top). (b) Stereological quantification of Iba1-positive cells (n = 5–8 per group). (c) Overview images of Iba1 immunohistochemistry (blue). (d) qPCR analysis of Cd11b, Cx3cr1, Hexb, P2ry12, and Trem2 from whole brain tissue of APPPS1;TK+/− mice compared with APPPS1;TK−/− controls (*, P = 0.03; **, P = 0.007; n = 6 per group). (e) Representative images of 4G8 immunohistochemistry. (f) Stereological quantification of the area covered by 4G8-positive plaques (n = 6–9 per group). (g and h) Congo red staining (g) and stereological quantification (h) of the area covered by Congo red–positive plaques (n = 6–9 per group). Bars: (a) 20 µm; (c, e, and g) 100 µm. (i) Amount of soluble and insoluble Aβ40 and Aβ42 and total Aβ40 and Aβ42 calculated from individual fractions measured by Meso Scale Diagnostics (measurements performed in duplicate from n = 5 biological replicates per group). (j) Representative Western blot images of APP, APPCTFβ, and APPCTFα in SDS fractions from brain homogenates described in i (6E10 detection; left) and representative quantification of Western blots (right; result representative for four independent experiments). All p-values >0.05 unless otherwise stated. All data are represented as mean ± SEM. All mice were treated icv for 10 d with GCV followed by a 28-d period without GCV administration.
Figure 3.
Figure 3.
Anti-Aβ antibodies fail to specifically promote plaque association or clearance by peripheral myeloid cells. (a) Representative images of Iba1 immunohistochemistry (blue) combined with pFTAA staining (green) are shown. (b) Stereological quantification of number of Iba1-positive cells (left; n = 5–6 per group) and quantification of Iba1-positive cell bodies per pFTAA area (right; n = 5–6 per group; ***, P = 0.0005). (c and e) Representative images of 4G8 immunohistochemistry (c) and Congo red staining (e). (a, c, and e) Bars, 100 µm. (d) Stereological quantification of the area covered by 4G8-positive plaques (top; **, P = 0.009) and number of 4G8-positive plaques (bottom; *, P = 0.02; n = 5–7 per group). (f) Stereological quantification of the number of Congo red–positive plaques (*, P = 0.02; n = 5–7 per group). (g) Amount of soluble and insoluble Aβ40 and Aβ42 and total Aβ40 and Aβ42 calculated from individual protein fractions (*, P = 0.04; measurements performed in duplicate from n = 5–7 biological replicates per group). (h) Representative image of Western blot analyses of APP, APPCTFβ, and APPCTFα in SDS-extracted brain fractions (APPct detection; left) and representative quantification of Western blots (right; result representative of six independent experiments). All data are represented as mean ± SEM.
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