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- (A), 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 A earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased A clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting A clearance.

1. Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology. 149 13th Street, Charlestown, Massachusetts 02129, USA.
2. Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
3. Department of Neurological Surgery, Okayama University Medical School 2-5-1, Shikata-cho, Okayama 700–8558, Japan.
4. Laboratory for Neurodegenerative and Aging Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
5. 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.

Correspondence to: Joseph El Khoury^1,2 e-mail: jelkhoury@partners.org

Correspondence to: Andrew D Luster¹ e-mail: luster.andrew@mgh.harvard.edu

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