4.6 Article

Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

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JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 5, 页码 3693-3706

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AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.135244

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资金

  1. National Institutes of Health [AG025500, AG031362]
  2. University of California Davis Alzheimer's Disease Center [AG010129]

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Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms of amyloid-beta protein (A beta), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar A beta, a major component of amyloid plaques in AD brains. Here we report that amyloid-beta oligomer (A beta O), at 5-50 nM, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca2+-activated potassium channel KCa3.1. A beta O treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor kappa B. Interestingly, although increasing nitric oxide (NO) production, A beta O did not increase several proinflammatory mediators commonly induced by lipopolyliposacharides or fibrillar A beta, suggesting that A beta O stimulates both common and divergent pathways of microglia activation. A beta O at low nanomolar concentrations, although not neurotoxic, induced indirect, microglia-mediated damage to neurons in dissociated cultures and in organotypic hippocampal slices. The indirect neurotoxicity was prevented by (i) doxycycline, an inhibitor of microglia activation; (ii) TRAM-34, a selective KCa3.1 blocker; and (iii) two inhibitors of inducible NO synthase, indicating that KCa3.1 activity and excessive NO release are required for A beta O-induced microglial neurotoxicity. Our results suggest that A beta O, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.

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