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Oligomeric amyloid ? induces IL-1? processing via production of ROS: implication in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive neuronal loss and cognitive decline. Oligomeric amyloid ? (oA?) is involved in the pathogenesis of AD by affecting synaptic plasticity and inhibiting long-term potentiation. Although several lines of evidence suggests that microglia, the resident immune cells in the central nervous system (CNS), are neurotoxic in the development of AD, the mechanism whether or how oA? induces microglial neurotoxicity remains unknown. Here, we show that oA? promotes the processing of pro-interleukin (IL)-1? into mature IL-1? in microglia, which then enhances microglial neurotoxicity. The processing is induced by an increase in activity of caspase-1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3) via mitochondrial reactive oxygen species (ROS) and partially via NADPH oxidase-induced ROS. The caspase-1 inhibitor Z-YVAD-FMK inhibits the processing of IL-1?, and attenuates microglial neurotoxicity. Our results indicate that microglia can be activated by oA? to induce neuroinflammation through processing of IL-1?, a pro-inflammatory cytokine, in AD.

SUBMITTER: Parajuli B

PROVIDER: S-EPMC3877570 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer's disease.

Parajuli B B Sonobe Y Y Horiuchi H H Takeuchi H H Mizuno T T Suzumura A A

Cell death & disease 20131219

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive neuronal loss and cognitive decline. Oligomeric amyloid β (oAβ) is involved in the pathogenesis of AD by affecting synaptic plasticity and inhibiting long-term potentiation. Although several lines of evidence suggests that microglia, the resident immune cells in the central nervous system (CNS), are neurotoxic in the development of AD, the mechanism whether or how oAβ induces microglial neurotoxicity rem ...[more]

PMID: 24357806

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Project description:Crystalline cellulose nanocrystals (CNCs) have emerged as novel materials for a wide variety of important applications such as nanofillers, nanocomposites, surface coatings, regenerative medicine and potential drug delivery. CNCs have a needle-like structure with sizes in the range of 100-200 nm long and 5-20 nm wide and a mean aspect ratio 10-100. Despite the great potential applicability of CNCs, very little is known about their potential immunogenicity. Needle-like materials have been known to evoke an immune response in particular to activate the (NOD-like receptor, pyrin domain-containing 3)-inflammasome/IL-1? (Interleukin 1?) pathway. In this study we evaluated the capacity of unmodified CNC and its cationic derivatives CNC-AEM (aminoethylmethacrylate)1, CNC-AEM2, CNC-AEMA(aminoethylmethacrylamide)1 and CNC-AEMA2 to stimulate NLRP3-inflammasome/IL-1? pathway and enhance the production of mitochondrial reactive oxygen species (ROS). Mouse macrophage cell line (J774A.1) was stimulated for 24 h with 50 µg/mL with unmodified CNC and its cationic derivatives. Alternatively, J774A1 or PBMCs (peripheral blood mononuclear cells) were stimulated with CNC-AEMA2 in presence or absence of LPS (lipopolysaccharide). IL-1? secretion was analyzed by ELISA, mitochondrial function by JC-1 staining and ATP content. Intracellular and mitochondrial reactive oxygen species (ROS) were assessed by DCF-DA (2',7'-dichlorodihydrofluorescein diacetate) and MitoSOX, respectively. Mitochondrial ROS and extracellular ATP were significantly increased in cells treated with CNC-AEMA2, which correlates with the strongest effects on IL-1? secretion in non-primed cells. CNC-AEMA2 also induced IL-1?secretion in LPS-primed and non-primed PBMCs. Our data suggest that the increases in mitochondrial ROS and ATP release induced by CNC-AEMA2 may be associated with its capability to evoke immune response. We demonstrate the first evidence that newly synthesized cationic cellulose nanocrystal derivative, CNC-AEMA2, has immunogenic properties, which may lead to the development of a potential non-toxic and safe nanomaterial to be used as a novel adjuvant for vaccines.

Dataset Information

Oligomeric amyloid ? induces IL-1? processing via production of ROS: implication in Alzheimer's disease.

Publications

Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer's disease.

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