期刊
NEUROBIOLOGY OF AGING
卷 58, 期 -, 页码 41-53出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2017.05.027
关键词
Alzheimer; Microglia; 5xFAD; Phagocytosis; Membrane currents; Purinergic responses; UDP; ATP; Abeta plaque
资金
- Deutsche Forschungsgemeinschaft [SFB TRR43, EXC 257 NeuroCure]
As the immunocompetent cells of the central nervous system, microglia accumulate at amyloid beta plaques in Alzheimer's disease (AD) and acquire a morphological phenotype of activated microglia. Recent functional studies, however, indicate that in mouse models of amyloidosis and AD, these cells are rather dysfunctional indicated by a reduced phagocytic activity. Here, we report that this reduction in phagocytic activity is associated with perturbed purinergic receptor signaling, since phagocytosis could be stimulated by P2Y(6) receptor activation in control, but not in 5xFAD transgenic animals, an animal model of amyloid deposition. Impaired phagocytosis is not innate, and develops only at later stages of amyloidosis. Furthermore, we show that membrane currents induced by uridine diphosphate, a ligand activating P2Y(6) receptors, are altered in response rate and amplitude in microglia in close vicinity to plaques, but not in plaque-free areas of 5xFAD animals. These changes were accompanied by changes in membrane properties and potassium channel activity of plaque-associated microglia in early and late stages of amyloidosis. As a conclusion, the physiological properties of plaque-associated microglia are altered with a strong impact on purinergic signaling. (C) 2017 Elsevier Inc. All rights reserved.
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