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

Joseph El Khoury*, Michelle Toft, Suzanne E. Hickman, Terry K. Means, Kinya Terada, Changiz Geula, Andrew D. Luster

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

622 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)432-438
Number of pages7
JournalNature Medicine
Volume13
Issue number4
DOIs
StatePublished - Apr 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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