Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity.
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-β protein (Aβ), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar Aβ, a major component of amyloid plaques in AD brains. Here we report that amyloid-β oligomer (AβO), at 5-50 nm, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca(2+)-activated potassium channel KCa3.1. AβO treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor κB. Interestingly, although increasing nitric oxide (NO) production, AβO did not increase several proinflammatory mediators commonly induced by lipopolyliposaccharides or fibrillar Aβ, suggesting that AβO stimulates both common and divergent pathways of microglia activation. AβO 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 AβO-induced microglial neurotoxicity. Our results suggest that AβO, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.
Maezawa
Izumi
I
Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, California 95618, USA.
Zimin
Pavel I
PI
Wulff
Heike
H
Jin
Lee-Way
LW
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D009569:Nitric Oxide