期刊
NEUROBIOLOGY OF AGING
卷 34, 期 4, 页码 1060-1068出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2012.08.009
关键词
Chemokine; Microglia; Phagocytosis; Memory function; Neurogenesis
资金
- National Institutes of Health [1P01 DA028555, 2R01 NS034239, 2R37 NS36126, P01 NS31492, P20RR 15635, P30 MH062261, P01MH64570, P01 NS43985]
- Carol Swarts Emerging Neuroscience Laboratory
- Department of Pharmacology and Experimental Neuroscience
- Frani and Louis Blumkin Foundation
- Baxter Healthcare
Neuroinflammation affects the pathobiology of Alzheimer's disease (AD). Notably, beta-amyloid (A beta) deposition induces microglial activation and the subsequent production of proinflammatory neurotoxic factors. In maintaining brain homeostasis, microglial plasticity also enables phenotypic transition between toxic and trophic activation states. One important control for such cell activation is through the CC-chemokine ligand 2 (CCL2) and its receptor, the CC-chemokine receptor 2. Both affect microglia and peripheral macrophage immune responses and for the latter, cell ingress across the blood-brain barrier. However, how CCL2-CC-chemokine receptor 2 signaling contributes to AD pathogenesis is not well understood. To this end, we now report that CCL2 deficiency influences behavioral abnormalities and disease progression in A beta precursor protein/presenilin-1 double-transgenic mice. Here, increased cortical and hippocampal A beta deposition is coincident with the formulation of A beta oligomers. Deficits in peripheral A beta clearance and in scavenger, neuroprogenitor, and microglial cell functions are linked to deficient A beta uptake. All serve to accelerate memory dysfunction. Taken together, these data support a role of CCL2 in innate immune functions relevant to AD pathogenesis. (C) 2013 Elsevier Inc. All rights reserved.
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