Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease.
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-beta (Abeta), 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 Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.
El Khoury
Joseph
J
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA. jelkhoury@partners.org
Toft
Michelle
M
Hickman
Suzanne E
SE
Means
Terry K
TK
Terada
Kinya
K
Geula
Changiz
C
Luster
Andrew D
AD
D000544:Alzheimer Disease / Q000276:immunology* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism*; D003433:Crosses, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000276:immunology
D016229:Amyloid beta-Peptides; C515335:Ccr2 protein, mouse; D018925:Chemokines; D054390:Receptors, CCR2