Szczepanik A M, Rampe D, Ringheim G E
Department of CNS, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey 08807-0800, USA.
J Neurochem. 2001 Apr;77(1):304-17. doi: 10.1046/j.1471-4159.2001.t01-1-00240.x.
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.
阿尔茨海默病（AD）的病理特征是含有β-淀粉样蛋白（Aβ）肽的老年斑，Aβ肽是一种具有神经毒性和激活胶质细胞免疫潜能的蛋白质。除了高度淀粉样蛋白生成性的肽Aβ（1-40/42）外，老年斑还含有氨基末端截短的Aβ肽，包括α分泌酶产生的p3片段Aβ（17-40/42）。在本研究中，在不同溶剂中老化的Aβ（17-40/42）、Aβ（1-40/42）、Aβ（1-16）和Aβ（25-35）表现出不同的激活小鼠小胶质细胞系MG-7的能力，这取决于溶剂、肽的“老化”以及与β-折叠形成没有严格相关性的肽序列。Aβ（17-40/42）或Aβ（1-42）刺激分化的人单核细胞（THP-1）产生促炎细胞因子白细胞介素（IL）-1α、IL-1β、IL-6和肿瘤坏死因子-α（TNF-α）以及趋化因子MCP-1，而其他Aβ片段几乎没有或没有观察到刺激作用。MG7细胞也会因Aβ（1-42）产生这五种促炎蛋白，而Aβ（17-40/42）主要诱导TNF-α和MCP-1。小鼠和人星形胶质细胞系（分别为D30和U373）对Aβ片段的反应通常较弱，对Aβ（1-42）或Aβ（17-40/42）片段主要产生IL-6和MCP-1。在小鼠中，脑室内注射Aβ（1-42）显著增加IL-1α、IL-1β、IL-6和MCP-1，而Aβ（17-40/42）增加MCP-1，Aβ（17-40）增加IL-1β。这些结果表明，p3和p4 Aβ片段是促炎胶质调节剂，因此可能在AD中观察到的免疫病理学发展中起作用。
