CCR5 deficiency induces astrocyte activation, Abeta deposit and impaired memory function.

Activation of astrocytes has been known to be associated with amyloid-beta (Abeta) deposit and production of pro-inflammatory cytokines and chemokines that lead to neuronal cell death in the pathogenesis of Alzheimer disease (AD). In the present study, we investigated whether the absence of CC chemokine receptor 5 (CCR5) results in activation of astrocytes, Abeta deposit and memory dysfunction in CCR5 knock (CCR5(-/-)) out mice. We found that long-term and spatial memory functions were impaired in CCR5(-/-) mice. There was a significant increased expression of glial fibrillary acidic protein (GFAP) in the brain of CCR5(-/-) mice as compared with that of wild type of CCR5 (CCR5(+/+)) mice. The expression of CCR5 was observed in CCR5(+/+) astrocytes, but was reduced in the CCR5(-/-) astrocytes even though the expression of GFAP was much higher. Paralleling with the activation of astorcytes, the Abeta(1-42) level was higher in the brains of CCR5(-/-) mice than that of CCR5(+/+) mice. Expression of beta-secretase (BACE1) and its product C99 was significantly elevated in CCR5(-/-) mice. The activation of CC chemokine receptor 2 (CCR2) causes activation of astrocytes that leads to Abeta deposit and memory dysfunction in CCR5(-/-) mice. In CCR5(-/-) mice, CCR2 expression was high and co-localized with GFAP. These findings suggest that the absence of CCR5 increases expression of CCR2, which leads to the activation of astrocytes causing Abeta deposit, and thereby impairs memory function. These results suggest that CCR5 may be a critical suppressor of the development and progression of AD pathology.