Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease
Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease
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DOI：
10.1038/78682
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发表时间：
2000-08-01
期刊：
影响因子：
82.9
通讯作者：
Yednock, T
中科院分区：
文献类型：
--
作者：
Bard, F;Cannon, C;Yednock, T
阿尔茨海默病的一个标志是淀粉样β肽在大脑中的积累及其作为斑块的沉积。由血小板衍生（PD）生长因子启动子驱动的淀粉样β前体蛋白（APP）微型基因转基因小鼠（PDAPP小鼠），过表达人类淀粉样前体蛋白的疾病相关突变形式之一，显示出阿尔茨海默病的许多病理学特征，包括细胞外淀粉样斑块的广泛沉积、星形细胞增多症和神经炎性营养不良（1，2）。用人淀粉样蛋白β肽主动免疫PDAPP小鼠可减少斑块负荷及其相关病理（3）。关于这种反应的机制已经提出了几种假设（4，5）。在这里我们报道了外周给予抗淀粉样β肽的抗体足以减少淀粉样蛋白负荷。尽管它们的血清水平相对适中，但被动施用的抗体能够进入中枢神经系统，装饰斑块并诱导预先存在的淀粉样蛋白的清除。当在用PDAPP或阿尔茨海默病脑组织切片的离体测定中检查时，针对淀粉样蛋白β-肽的抗体触发小胶质细胞通过Fc受体介导的吞噬作用和随后的肽降解来清除斑块。这些结果表明，抗体可以穿过血脑屏障直接作用于中枢神经系统，应被视为治疗阿尔茨海默病和其他神经系统疾病的治疗方法。
One hallmark of Alzheimer disease is the accumulation of amyloid beta -peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy(1,2). Active immunization of PDAPP mice with human amyloid beta -peptide reduces plaque burden and its associated pathologies(3). Several hypotheses have been proposed regarding the mechanism of this response(4,5). Here we report that peripheral administration of antibodies against amyloid beta -peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta -peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.