Hydrogen Sulfide Protects Amyloid-β Induced Cell Toxicity in Microglia
Hydrogen Sulfide Protects Amyloid-β Induced Cell Toxicity in Microglia
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DOI：
10.3233/jad-2010-101002
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Bian, Jin-Song
中科院分区：
文献类型：
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作者：
Liu, Yan-Ying;Bian, Jin-Song
阿尔茨海默病(AD)的病理特征是老年斑的积聚，其中包含激活的小胶质细胞和淀粉样β蛋白多肽(Aβ)。我们发现聚集的Aβ(1-40)肽(25mM，24小时)显著降低BV-2小胶质细胞的存活率。NaHS(硫化氢(H_2S)供体，25-500亩M)可浓度依赖性地减弱这一作用。NaHS还显著减弱了Aβ诱导的LDH释放和生长停滞DNA损伤的蛋白质表达上调(Gadd153)。这些数据表明，硫化氢可能会减弱Aβ诱导的细胞毒性和细胞周期重新进入。NaHS还可抑制一氧化氮的释放和诱导型一氧化氮合酶的上调。外源NaHS或半胱硫氨酸β合酶激活剂S-腺苷-L-蛋氨酸刺激内源H_2S的产生均可减弱上述效应。NaHS还可通过阻断p38和JNK-MAPK来抑制环氧合酶2的蛋白表达上调，从而减少肿瘤坏死因子-α的释放。此外，Aβ可诱导线粒体成员潜能丧失(Delta Psim)，并激活p38-、JNK-和ERK-MAPKs。应用NaHS可减弱这些效应，但不影响ERK的激活。综上所述，我们首次证明了H_2S可能通过抑制炎症、促进细胞生长和保护线粒体功能来保护细胞免受Aβ诱导的细胞损伤，这种保护作用依赖于p38和JNK-MAPK。我们的结果提示，硫化氢可能对AD有潜在的治疗价值。
Alzheimer's disease (AD) is pathologically characterized by the accumulation of senile plaques, containing activated microglia and amyloid-beta peptides (A beta). We found that aggregated A beta(1-40) peptide (25 mu M, 24 h) significantly decreased viability of BV-2 microglial cells. This was concentration-dependently attenuated by NaHS (a hydrogen sulfide (H2S) donor, 25-500 mu M). NaHS also significantly attenuated A beta-induced LDH release and the up-regulation of protein expression of growth arrest DNA damage (GADD 153). These data suggest that H2S may attenuate A beta-induced cell toxicity and cell cycle re-entry. Pretreatment with NaHS also suppressed the release of nitric oxide and the upregulation of inducible nitric oxide synthase. These effects were attenuated by exogenous application of NaHS or stimulation of endogenous generation of H2S with S-adenosyl-L-methionine, a cystathionine beta synthase activator. NaHS also decreased the releases of TNF-alpha and suppressed the up-regulation of protein expression of cyclooxygenase 2, which were mimicked by blockade of p38 and JNK-MAPK. In addition, A beta induced loss of mitochondrial member potential (Delta Psi m) and activation of p38-, JNK-, and ERK-MAPKs. Application of NaHS attenuated these effects but failed to affect the activation of ERK. In conclusion, we demonstrated for the first time that H2S may protect cell against A beta-induced cell injury by inhibition of inflammation, promotion of cell growth and preservation of mitochondrial function in a p38- and JNK-MAPK dependent manner. Our results suggest that H2S may have potential therapeutic value for treatment of AD.