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Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease

Nature Medicine volume 13, pages 432–438 (2007)Cite this article

Abstract

Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-β (Aβ), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Aβ earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Aβ clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Aβ clearance.

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Figure 1: Decreased survival of Ccr2-deficient APP mice correlates with levels of Ccr2 expression.
Figure 2: Increased brain Aβ levels in Ccr2-deficient APP mice is associated with perivascular Aβ deposition and decreased neprilysin (Mme) expression.
Figure 3: Absence of microglial accumulation in Ccr2-deficient APP mice.
Figure 4: Flow cytometry analysis of wild-type, Ccr2+/−, APP and APP-Ccr2+/− mice confirms absence of microglial accumulation in Ccr2-deficient APP mice.
Figure 5: Ccr2 deficiency does not affect Aβ binding to microglia, Aβ-induced activation or the ability of microglia and macrophages to proliferate in response to LPS stimulation in vivo.
Figure 6: Ccr2 deficiency abolishes macrophage chemotaxis to supernatants from Aβ-stimulated macrophages and microglial accumulation at sites of stereotaxic Aβ microinjection.

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Acknowledgements

We thank D. Selkoe for discussing the data and for suggestions, K. Hsiao-Ashe for permission to use the APP mice, I. Charo (Gladstone Institute of Cardiovascular Disease) for providing the Ccr2−/− mice, the Harvard Center for Neurodegeneration and Repair for funding J.E.K. and C.G., the American Health Assistance Foundation and the Dana Foundation for funding J.E.K. and the US National Institutes of Health for funding J.E.K. and A.D.L.

Author information

Author notes

  1. Changiz Geula

    Present address: Present address: Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Searle 11-465, Chicago, Illinois 60611, USA.,

Authors and Affiliations

  1. Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Allergy and Immunology, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Joseph El Khoury, Michelle Toft, Suzanne E Hickman, Terry K Means & Andrew D Luster

  2. Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Joseph El Khoury

  3. Department of Neurological Surgery, Okayama University Medical School 2-5-1, Shikata-cho, 700–8558, Okayama, Japan

    Kinya Terada

  4. Laboratory for Neurodegenerative and Aging Research, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Changiz Geula

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Contributions

J.E.K. designed the experiments, analyzed the data, wrote the manuscript, performed the chemotaxis experiments and directly supervised M.T. in breeding the mice and in performing the immunostaining and the ELISA experiments. S.E.H. isolated brain cells and macrophages and performed the Aβ binding experiments, and the laser capture microdissection experiments. T.K.M. performed the Q-PCR. S.E.H. and T.K.M. were also involved in detailed discussions of the data and manuscript. K.T. and C.G. designed and performed the stereotaxic microinjection experiments. A.D.L. participated in designing experiments, evaluating data and writing the manuscript.

Corresponding authors

Correspondence to Joseph El Khoury or Andrew D Luster.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Florid Aβ deposition and senile plaque formation in aged APP mice. (PDF 72 kb)

Supplementary Fig. 2

Ccl2 is produced in Cd11b-positive cells in APP mice but not in Gfap-positive cells. (PDF 766 kb)

Supplementary Fig. 3

Expression of Ccr2 correlates with Cd11b expression in brain cells. (PDF 331 kb)

Supplementary Fig. 4

Absence of microglial accumulation in 65-day old Ccr2 deficient APP mice. (PDF 73 kb)

Supplementary Fig. 5

Migration of resident peritoneal macrophages from Ccr2+/−, Ccr2−/−, and WT mice to Ccl2 and Ccl3. (PDF 75 kb)

Supplementary Table 1

Sequences of primers used for Q-PCR. (PDF 51 kb)

Supplementary Methods (PDF 114 kb)

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El Khoury, J., Toft, M., Hickman, S. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13, 432–438 (2007). https://doi.org/10.1038/nm1555

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