Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia.
Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia.
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DOI：
10.1186/1742-2094-6-1
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发表时间：
2009-01-05
影响因子：
9.3
通讯作者：
Combs, Colin K.
中科院分区：
文献类型：
--
作者：
Sondag, Cindy M.;Dhawan, Gunjan;Combs, Colin K.
β淀粉样蛋白（Aβ）肽是阿尔茨海默病脑中存在的老年斑的主要成分。发病机制与肽的聚集形式相关，因为这些原纤维是在斑块中容易发现的构象。然而，最近的研究表明，Aβ的非聚集的可溶性组装体具有刺激神经元功能障碍的潜力，并且可能在阿尔茨海默病的发病机制中发挥重要作用。制备可溶性合成Aβ1-42寡聚体，通过SDS-PAGE评估主要产生二聚体-三聚体构象。类似的分析表明，原纤维制备产生大的不溶性聚集体，不能迁移出凝胶的堆叠部分。这些肽制剂用于刺激原代鼠小胶质细胞和皮质神经元培养物。通过Western分析和ELISA分析小胶质细胞的信号应答和分泌表型的变化。通过定量乳酸脱氢酶从培养物中的释放来检查活力。使用Aβ寡聚体和原纤维刺激小胶质细胞进行比较。低聚物和原纤维都刺激了初级小胶质细胞的促炎激活，但肽的特定构象决定了激活曲线。与原纤维相比，寡聚体刺激活性、磷酸化的林恩和Syk激酶以及p38 MAP激酶的水平增加。此外，寡聚体刺激白细胞介素6，单核细胞趋化蛋白-1和角质形成细胞趋化因子相比，原纤维的差异分泌配置文件。最后，可溶性低聚物刺激培养的皮层神经元的死亡，加剧了小胶质细胞的存在。这些数据表明，原纤维和寡聚体刺激小胶质细胞中独特的信号传导反应，导致离散的分泌变化和对神经元存活的影响。这表明疾病期间的炎症变化可能是独特的肽刺激事件的结果，并且每个构象可能代表单独的抗炎治疗靶点。
Beta amyloid (Aβ) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies have shown that the nonaggregated, soluble assemblies of Aβ have the potential to stimulate neuronal dysfunction and may play a prominent role in the pathogenesis of Alzheimer's disease. Soluble, synthetic Aβ1–42 oligomers were prepared producing mainly dimer-trimer conformations as assessed by SDS-PAGE. Similar analysis demonstrated fibril preparations to produce large insoluble aggregates unable to migrate out of the stacking portion of the gels. These peptide preparations were used to stimulate primary murine microglia and cortical neuron cultures. Microglia were analyzed for changes in signaling response and secretory phenotype via Western analysis and ELISA. Viability was examined by quantifying lactate dehydrogenase release from the cultures. Aβ oligomers and fibrils were used to stimulate microglia for comparison. Both the oligomers and fibrils stimulated proinflammatory activation of primary microglia but the specific conformation of the peptide determined the activation profile. Oligomers stimulated increased levels of active, phosphorylated Lyn and Syk kinase as well as p38 MAP kinase compared to fibrils. Moreover, oligomers stimulated a differential secretory profile for interleukin 6, monocyte chemoattractant protein-1 and keratinocyte chemoattractant when compared to fibrils. Finally, soluble oligomers stimulated death of cultured cortical neurons that was exacerbated by the presence of microglia. These data suggest that fibrils and oligomers stimulate unique signaling responses in microglia leading to discrete secretory changes and effects on neuron survival. This suggests that inflammation changes during disease may be the consequence of unique peptide-stimulated events and each conformation may represent an individual anti-inflammatory therapeutic target.
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影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
DOI：
10.1073/pnas.96.6.3228
发表时间：
1999-03-16
影响因子：
11.1
作者：
Hsia, AY;Masliah, E;Mucke, L
通讯作者：
Mucke, L
影响因子：
2.9
作者：
Chromy, BA;Nowak, RJ;Klein, WL
通讯作者：
Klein, WL
影响因子：
82.9
作者：
Klyubin, I;Walsh, DM;Rowan, MJ
通讯作者：
Rowan, MJ
影响因子：
5.3
作者：
Hartley, DM;Walsh, DM;Selkoe, DJ
通讯作者：
Selkoe, DJ