Amyloid-beta peptide fragments p3 and p4 induce pro-inflammatory cytokine and chemokine production in vitro and in vivo.
Amyloid-beta peptide fragments p3 and p4 induce pro-inflammatory cytokine and chemokine production in vitro and in vivo.
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DOI：
10.1046/j.1471-4159.2001.t01-1-00240.x
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发表时间：
2001-04
影响因子：
4.7
通讯作者：
A. M. Szczepanik;D. Rampe;G. Ringheim
中科院分区：
文献类型：
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作者：
A. M. Szczepanik;D. Rampe;G. Ringheim
阿尔茨海默病（AD）病理学特征在于含有淀粉样蛋白-β（A β）肽的老年斑，淀粉样蛋白-β（A β）肽是具有神经毒性和神经胶质免疫激活潜力的蛋白质。除了高度淀粉样蛋白生成肽A β（1--40/42）外，斑块还含有氨基末端截短的A β肽，包括α分泌酶产生的p3片段A β（17--40/42）。在本研究中，在不同溶剂中老化的A β（17- 40/42）、A β（1- 40/42）、A β（1- 16）和A β（25- 35）表现出不同的激活鼠小胶质细胞系MG-7的能力，这取决于溶剂、肽“老化”和与β折叠形成不严格相关的肽序列。A β（17- 40/42）或A β（1- 42）刺激促炎细胞因子白细胞介素（IL）-1 α、IL-1 β、IL-6和肿瘤坏死因子-α（TNF-α）以及来自分化的人单核细胞（THP-1）的趋化因子MCP-1的产生，而用其它A β片段观察到很少或没有刺激。MG 7细胞也响应于A β（1-42）产生这五种促炎蛋白，而A β（17- 40/42）主要引起TNF-α和MCP-1。小鼠和人星形胶质细胞细胞系（分别为D30和U373）通常对A β片段的反应较低，响应A β（1--42）或A β（17--40/42）片段，主要产生IL-6和MCP-1。在小鼠中，脑室内输注A β（1- 42）显著增加IL-1 α、IL-1 β、IL-6和MCP-1，而A β（17- 40/42）增加MCP-1，A β（17- 40）增加IL-1 β。这些结果表明，p3和p4 A β片段是促炎性神经胶质调节剂，因此可能在AD中观察到的免疫病理学的发展中发挥作用。
Alzheimer's disease (AD) pathology is characterized by senile plaques containing amyloid-beta (A beta) peptide, a protein with neurotoxic and glial immune activating potential. In addition to the highly amyloidogenic peptides A beta(1--40/42), plaques contain amino-terminal truncated A beta peptides including the alpha secretase-generated p3 fragments A beta(17--40/42). In the present study, A beta(17--40/42), A beta(1--40/42), A beta(1--16), and A beta(25--35) aged in different solvents exhibited varying capacity to activate the murine microglia cell line MG-7 depending on solvent, peptide 'aging', and peptide sequence that did not strictly correlate with beta-sheet formation. A beta(17--40/42) or A beta(1--42) stimulated production of the pro-inflammatory cytokines interleukin (IL)-1 alpha, IL-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha), and the chemokine MCP-1 from differentiated human monocytes (THP-1) while little or no stimulation was observed with the other A beta fragments. MG7 cells also produced these five pro-inflammatory proteins in response to A beta(1-42) whereas A beta(17--40/42) elicited mainly TNF-alpha and MCP-1. Murine and human astrocyte cell lines (D30 and U373, respectively) were generally less responsive to A beta fragments producing mainly IL-6 and MCP-1 in response to A beta(1--42) or A beta(17--40/42) fragments. In mice, an intracerebroventricular infusion of A beta(1--42) significantly increased IL-1 alpha, IL-1 beta, IL-6 and MCP-1 while A beta(17--40/42) increased MCP-1 and A beta(17--40) increased IL-1 beta. These results demonstrate that p3 and p4 A beta fragments are pro-inflammatory glial modulators and thus may play a role in development of the immunopathology observed in AD.