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Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity.

ABSTRACT: 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-? protein (A?), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar A?, a major component of amyloid plaques in AD brains. Here we report that amyloid-? oligomer (A?O), 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. A?O treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor ?B. Interestingly, although increasing nitric oxide (NO) production, A?O did not increase several proinflammatory mediators commonly induced by lipopolyliposaccharides or fibrillar A?, suggesting that A?O stimulates both common and divergent pathways of microglia activation. A?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?O-induced microglial neurotoxicity. Our results suggest that A?O, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.

SUBMITTER: Maezawa I

PROVIDER: S-EPMC3030372 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity.

Maezawa Izumi I Zimin Pavel I PI Wulff Heike H Jin Lee-Way LW

The Journal of biological chemistry 20101022 5

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 require ...[more]

PMID: 20971854

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Project description:BackgroundMicroglia-mediated neuroinflammation is important in Alzheimer's disease (AD) pathogenesis. Extracellular deposition of β-amyloid (Aβ), a major pathological hallmark of AD, can induce microglia activation. Adiponectin (APN), an adipocyte-derived adipokine, exerts anti-inflammatory effects in the periphery and brain. Chronic APN deficiency leads to cognitive impairment and AD-like pathologies in aged mice. Here, we aim to study the role of APN in regulating microglia-mediated neuroinflammation in AD.MethodsInflammatory response of cultured microglia (BV2 cells) to AβO and effects of APN were studied by measuring levels of proinflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1β [IL-1β]) in cultured medium before and after exposure to AβO, with and without APN pretreatment. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) were targeted by small interference RNA. To study the neuroprotective effect of APN, cultured HT-22 hippocampal cells were treated with conditioned medium of AβO-exposed BV2 cells or were co-cultured with BV2 cells in transwells. The cytotoxicity of HT-22 hippocampal cells was assessed by MTT reduction. We generated APN-deficient AD mice (APN-/-5xFAD) by crossing APN-knockout mice with 5xFAD mice to determine the effects of APN deficiency on microglia-mediated neuroinflammation in AD.ResultsAdipoR1 and AdipoR2 were expressed in BV2 cells and microglia of mice. Pretreatment with APN for 2 h suppressed TNFα and IL-1β release induced by AβO in BV2 cells. Additionally, APN rescued the decrease of AMPK phosphorylation and suppressed nuclear translocation of nuclear factor kappa B (NF-κB) induced by AβO. Compound C, an inhibitor of AMPK, abolished these effects of APN. Knockdown of AdipoR1, but not AdipoR2 in BV2 cells, inhibited the ability of APN to suppress proinflammatory cytokine release induced by AβO. Moreover, pretreatment with APN inhibited the cytotoxicity of HT-22 cells co-cultured with AβO-exposed BV2 cells. Lastly, APN deficiency exacerbated microglia activation in 9-month-old APN-/-5xFAD mice associated with upregulation of TNFα and IL-1β in the cortex and hippocampus.ConclusionsOur findings demonstrate that APN inhibits inflammatory response of microglia to AβO via AdipoR1-AMPK-NF-κB signaling, and APN deficiency aggravates microglia activation and neuroinflammation in AD mice. APN may be a novel therapeutic agent for inhibiting neuroinflammation in AD.

Dataset Information

Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity.

Publications

Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity.

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