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. 2015 Oct 19;212(11):1803-9.
doi: 10.1084/jem.20150478. Epub 2015 Oct 12.

Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer's disease

Nicholas H Varvel  1 , Stefan A Grathwohl  2 , Karoline Degenhardt  1 , Claudia Resch  1 , Andrea Bosch  1 , Mathias Jucker  1 , Jonas J Neher  3
Affiliations

Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer's disease

Nicholas H Varvel et al. J Exp Med. .

Abstract

Immune cells of myeloid lineage are encountered in the Alzheimer's disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.

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Figures

Figure 1.
Figure 1.
Long-term myeloid cell replacement does not alter Aβ deposition. Analysis of the effects of myeloid cell replacement in two APP transgenic mouse models, APPPS1 and APP23. (a) Brain-resident myeloid cells were ablated in 3-mo-old, depositing APPPS1 mice, which then remained untreated for 2 or 12 wk. Immunostaining shows Iba1-positive myeloid cells and amyloid plaques (Congo red) in APPPS1/TK− mice (top) and APPPS1/TK+ mice (bottom). (b) Stereological quantification of congophilic deposits (Congo red staining) and total Aβ load (anti-Aβ staining) at 2 or 12 wk after GCV treatment in APPPS1/TK− mice compared with repopulated APPPS1/TK+ animals. (c) Stereological analysis of total Iba1+ cells in APPPS1/TK+ compared with APPPS1/TK− mice (ANOVA: transgene × time point interaction, F(3,25) = 6.417, P < 0.001; Tukey’s HSD post hoc: *, P < 0.05). (d) Amyloid-associated neuritic dystrophy in APPPS1/TK+ and APPPS1/TK− mice (Congo red and APP staining). (e) 9-mo-old, depositing APP23/TK mice received GCV treatment and then remained untreated for 6 mo. Immunostaining shows Iba1-positive myeloid cells and amyloid plaques (Congo red). (f) Stereological quantification of congophilic deposits and total Aβ load. (g) Stereological analysis of cortical Iba1-positive cells in APP23/TK− compared with APP23/TK+ mice. (h) Amyloid-associated neuritic dystrophy in APP23/TK+ and APP23/TK− mice (Congo red and APP staining). (i) APP23/TK mice at 5 mo of age, i.e., before onset of plaque deposition, received GCV treatment and then remained untreated for 5 mo. Immunostaining shows Iba1-positive myeloid cells and amyloid plaques (Congo red). (bottom right, top picture) Iba1 staining after initial depletion; (bottom picture) myeloid cell morphology upon invasion. (a, e, and i) Insets show higher-magnification images. (j) Stereological quantification of total Aβ load and total number of congophilic deposits in APP23 animals. (k) Quantitative stereological analysis of Iba1-positive cells in APP23/TK+ and APP23/TK− animals. Bars: (a, e, and i) 100 µm; (d and h) 50 µm. Data were pooled from at least two independent experiments. Analyses were performed in a–d for APPPS1/TK−: n = 7/8 males and APPPS1/TK+: n = 6/5 males for the 2+2/2+12 wk time points, respectively; in e–h for APP23/TK+: n = 4 females, 3 males and APP23/TK−: n = 4 females, 2 males; and i–k for APP23/TK+: n = 4 males and APP23/TK−: n = 7 males. Immunostainings were independently replicated at least two times. Data are presented as mean ± SEM.
Figure 2.
Figure 2.
Trem2 expression in myeloid cells occurs with plaque association. (a) Trem2 expression is observed in myeloid cells (Iba1 positive) associated with plaques (stained with Methoxy-X04) in APP23 (shown) and APPPS1 mice (not depicted). Images are maximum projections of confocal z-stacks (insets show representative high-magnification images of a single confocal plane in plaque-associated cells). (b) Maximum projection of confocal z-stack in 4-mo-old APPPS1/TK− animals shows Iba1-positive cells expressing Trem2 in APPPS1/TK− animals, whereas nonplaque-associated infiltrating monocytes do not express Trem2 in APPPS1/TK+ mice. (c) APP23/TK− as well as APP23/TK+ animals repopulated before Aβ deposition show plaque-associated myeloid cells positive for Trem2 at the age of 10 mo. Bars: (a) 30 µm; (b and c) 20 µm. Immunostaining was performed for n ≥ 4 randomly chosen animals and replicated three times.
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