Amyloid β plaque-associated proteins C1q and SAP enhance the Aβ1–42 peptide-induced cytokine secretion by adult human microglia in vitro
Amyloid β plaque-associated proteins C1q and SAP enhance the Aβ1–42 peptide-induced cytokine secretion by adult human microglia in vitro
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DOI：
10.1007/s00401-002-0624-7
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发表时间：
2003-02
影响因子：
12.7
通讯作者：
R. Veerhuis;M. V. van Breemen;J. Hoozemans;M. Morbin;Jamal Ouladhadj;F. Tagliavini;P. Eikelenboom
中科院分区：
文献类型：
--
作者：
R. Veerhuis;M. V. van Breemen;J. Hoozemans;M. Morbin;Jamal Ouladhadj;F. Tagliavini;P. Eikelenboom
由活化的小胶质细胞释放的促炎细胞因子可能是阿尔茨海默病（AD）病理学的驱动力。我们评估了Aβ沉积物中补体因子C1 q和血清淀粉样蛋白P成分（SAP）的存在是否与小胶质细胞活化有关。激活的小胶质细胞在AD颞叶皮质SAP和C1 q免疫反应性纤维状淀粉样蛋白β（Aβ）斑块中积累。在AD尾状核和非痴呆对照颞叶皮层的SAP和C1 q阳性外切、非纤维状、tau阴性Aβ斑块中未观察到成簇的小胶质细胞。此外，在AD尾状核和非痴呆对照颞叶皮质中的C1 q和SAP阴性、不规则形状、弥漫性斑块中未观察到成簇的小胶质细胞，这表明小胶质细胞在具有一定纤维性的Aβ沉积物中被吸引和激活，此外，还具有固定的SAP和C1 q。因此，在体外评估了Aβ1-42、SAP和C1 q对人死后小胶质细胞分泌细胞因子的影响。Aβ1- 42单独给药几乎没有影响。Aβ1- 42肽联合C1 q或C1 q和SAP分别使小胶质细胞IL-6分泌增加4倍和8倍。小胶质细胞暴露于Aβ1-42-SAP-C1 q复合物后，肿瘤坏死因子（TNF）-α以及细胞内IL-1α和IL-1β水平也升高。结合早期的发现，即淀粉样蛋白和活化的小胶质细胞在AD患者认知功能下降的相对早期阶段积累，这表明SAP和C1 q中含有Aβ沉积物的活化的分泌精氨酸的小胶质细胞聚集在AD的神经退行性变化之前，因此可能提供“治疗窗口”。
Pro-inflammatory cytokines released by activated microglia could be a driving force in Alzheimer's disease (AD) pathology. We evaluated whether the presence of complement factor C1q and serum amyloid P component (SAP) in Aβ deposits is related to microglial activation. Activated microglia accumulate in SAP- and C1q-immunoreactive fibrillar amyloid β (Aβ) plaques in AD temporal cortex. No clustered microglia are seen in SAP- and C1q-positive circumscript, non-fibrillar, tau-negative Aβ plaques in AD caudate nucleus and non-demented control temporal cortex. In addition, no clustered microglia were observed in C1q- and SAP-negative, irregular shaped, diffuse plaques in AD caudate nucleus and in non-demented control temporal cortex, which suggests that microglia are attracted and activated in Aβ deposits of certain fibrillarity that, in addition, have fixed SAP and C1q. Therefore, the effects of Aβ1–42, SAP and C1q on cytokine secretion by human postmortem microglia in vitro were assessed. Aβ1–42alone had little to no effect. Aβ1–42peptides in combination with C1q or C1q and SAP increased microglial interleukin (IL)-6 secretion four- and eightfold, respectively. Tumor necrosis factor (TNF)-α, as well as intracellular IL-1α and IL-1β levels, also increased upon exposure of microglia to Aβ1–42-SAP-C1q complexes. Combined with earlier findings, that amyloid and activated microglia accumulate at a relatively early stage of cognitive decline in AD patients, this suggests that clustering of activated, cytokine-secreting microglia in SAP- and C1q-containing Aβ deposits precedes neurodegenerative changes in AD, and thus may provide a "therapeutic window".