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. 2013;8(4):e60921.
doi: 10.1371/journal.pone.0060921. Epub 2013 Apr 8.

Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology

Grietje Krabbe  1 , Annett Halle, Vitali Matyash, Jan L Rinnenthal, Gina D Eom, Ulrike Bernhardt, Kelly R Miller, Stefan Prokop, Helmut Kettenmann, Frank L Heppner
Affiliations

Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology

Grietje Krabbe et al. PLoS One. 2013.

Abstract

Microglial cells closely interact with senile plaques in Alzheimer's disease and acquire the morphological appearance of an activated phenotype. The significance of this microglial phenotype and the impact of microglia for disease progression have remained controversial. To uncover and characterize putative changes in the functionality of microglia during Alzheimer's disease, we directly assessed microglial behavior in two mouse models of Alzheimer's disease. Using in vivo two-photon microscopy and acute brain slice preparations, we found that important microglial functions - directed process motility and phagocytic activity - were strongly impaired in mice with Alzheimer's disease-like pathology compared to age-matched non-transgenic animals. Notably, impairment of microglial function temporally and spatially correlated with Aβ plaque deposition, and phagocytic capacity of microglia could be restored by interventionally decreasing amyloid burden by Aβ vaccination. These data suggest that major microglial functions progressively decline in Alzheimer's disease with the appearance of Aβ plaques, and that this functional impairment is reversible by lowering Aβ burden, e.g. by means of Aβ vaccination.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Lesion-directed microglial process movement is impaired in a mouse model of cerebral amyloidosis.
(A) Representative intravital two-photon microscopy images and (B) time course of microglial process movement towards a laser-induced micro-lesion (dashed circle) in 8 month old live anaesthetized APPPS1-Cx3cr1 +/gfp (n = 6) and Cx3cr1 +/gfp mice (n = 8). Aβ plaques are stained with Methoxy-XO4 (blue, *). (C) Representative images and (D) relative microglial response to laser lesions in acute cortical cerebral slices of 10 month old APPPS1-Cx3cr1 +/gfp (n = 8) and Cx3cr1 +/gfp (n = 7) mice. Aβ plaques are stained with Thiazine Red (red, *). Data are mean ± s.e.m, *p<0.05. Scale bars: 10 µm. a.u. = arbitrary units.
Figure 2
Figure 2. Phagocytic capacity of cortical microglia is impaired in two mouse models of cerebral amyloidosis.
(A) Representative images (left) and microglial phagocytic index (in arbitrary units, a.u., right) of 9 month old APPPS1 mice and wildtype littermate controls (3 mice per genotype; p<0.001). Images show microglia (Iba-1, red), Aβ (4G8, blue) and fluorescent microspheres (green). Orthogonal views of z-stack images are shown in the bottom panel. (B) Representative images (left) and microglial phagocytic index of 20 month old APP23 and age-matched control mice (3 mice per genotype, p<0.001, right) are shown. Data are mean ± s.e.m, ***p<0.001. Scale bars: 10 µm.
Figure 3
Figure 3. Impairment of microglial phagocytosis in APPPS1 mice correlates with Aβ plaque deposition.
(A) Aβ plaque load (brain area covered by Thiazine red-positive plaques) and relative microglial phagocytic activity normalized to corresponding wildtype littermate in the cortex of 7–9 week, 4 and 9 month old APPPS1 mice. 7–9 week old mice were sub-classified according to apparent 4G8 positive plaque deposition as with (+) or without (−) detectable plaque load. (B) Correlation between extent of plaque load and relative microglial phagocytic activity in the cortex of APPPS1 mice. (C, D) Thiazine red-covered area and relative phagocytic activity of microglia in the hippocampus of 7–9 week and 4 month old mice (C) and in the cerebellum of 4 month old APPPS1 mice (D). Absolute values of microglial phagocytic indices from APPPS1 mice were normalized to wildtype littermate controls (3–4 mice per age group and genotype, ***p<0.001). (E) Phagocytic index (3 independent experiments, p = 0.181) and representative images of primary microglial cultures from wildtype and APPPS1 mice. Microglia (Iba-1, red), nuclei (DRAQ5, blue) and microspheres (green). All data are mean ± s.e.m, *p<0.05, **p<0.01. a.u. = arbitrary units. Scale bars: 10 µm.
Figure 4
Figure 4. Passive anti-Aβ vaccination reduces plaque burden and restores hippocampal microglial phagocytic activity.
5 month old APPPS1 mice (n = 3 mice per group) and wildtype littermates (n = 2 mice per group) were biweekly injected intraperitoneally with IgG (black bar) or anti-Aβ antibody (Ab9, grey bar) for 6 weeks. The area covered by Thiazine Red-positive Aβ plaques in cortex (A) and hippocampus (B) of 6.5 month old APPPS1 mice or age-matched controls treated with IgG or Ab9 is shown in the left panel. Absolute values of microglial phagocytic indices in the cortex (A) and hippocampus (B) of the same mice are depicted on the right panel. All data are mean ± s.e.m, *p<0.05, **p<0.01. a.u. = arbitrary units.
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References

    1. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314–1318. - PubMed
    1. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8: 752–758. - PubMed
    1. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29: 3974–3980. - PMC - PubMed
    1. Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77: 10–18. - PubMed
    1. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, et al. (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7: 483–495. - PMC - PubMed

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