Interleukin-1β mediated amyloid plaque clearance is independent of CCR2 signaling in the APP/PS1 mouse model of Alzheimer's disease

Neuroinflammation is a key component of Alzheimer's disease (AD) pathogenesis. Particularly, the proinflammatory cytokine interleukin-1 beta (IL-1 beta) is upregulated in human AD and believed to promote amyloid plaque deposition. However, studies from our laboratory have shown that chronic IL-1 beta overexpression in the APPswe/PSEN1dE9 (APP/PS1) mouse model of AD ameliorates amyloid pathology, increases plaque-associated microglia, and induces recruitment of peripheral immune cells to the brain parenchyma. To investigate the contribution of CCR2 signaling in IL-1 beta-mediated amyloid plaque clearance, seven month-old APP/PS1/CCR2(-/-) mice were intrahippocampally transduced with a recombinant adeno-associated virus serotype 2 containing the cleaved form of human IL-1 beta (rAAV2-IL-1 beta). Four weeks after rAAV2-IL-1 beta transduction, we found significant reductions in 6E10 and Congo red staining of amyloid plaques that was confirmed by decreased levels of insoluble A beta(1-42) and A beta(1-40) in the inflamed hippocampus. Bone marrow chimeric studies confirmed the presence of infiltrating immune cells following IL-1 beta overexpression and revealed that dramatic reduction of CCR2(+) peripheral mononuclear cell recruitment to the inflamed hippocampus did not prevent the ability of IL-1 beta to induce amyloid plaque clearance. These results suggest that infiltrating CCR2(+) monocytes do not contribute to IL-1 beta-mediated amyloid plaque clearance. (C) 2014 Elsevier Inc. All rights reserved.