Morgan Dave
Alzheimer Research Laboratory, Department of Pharmacology, College of Medicine, University of South Florida, Tampa, FL 33612-4799, USA.
Neurodegener Dis. 2005;2(5):261-6. doi: 10.1159/000090366.
Alzheimer's disease is a major health problem with limited available medical treatment options. Immunotherapy is one approach with the potential to slow or reverse the disease process. In transgenic mouse models of amyloid deposition, anti-A beta immunotherapy is remarkably effective at diminishing the amyloid burden and reversing the memory deficiency phenotype present in these mice. Three distinct mechanisms of antibody action have been proposed to mediate these benefits of anti-A beta immunotherapy. The first is a catalytic dissolution of the A beta fibrils, proposed by Beka Solomon and colleagues. A second mechanism is opsonization of the amyloid by the antibody and subsequent phagocytosis by macrophages proposed by Dale Schenk and the Elan group. A third mechanism proposed by DeMattos, Holtzman and colleagues is the peripheral sink hypothesis, arguing that circulating antibodies sequester A beta and favor efflux of A beta from the CNS over influx to the CNS. None of these mechanisms are mutually exclusive. Our research group has evaluated these mechanisms using intracranial injection and systemic administration of anti-A beta antibodies. We found evidence supporting all three mechanisms, and suggest they may act synergistically to achieve the large effect size of the immunotherapeutic approach. However, in aged amyloid precursor protein transgenic mice administered anti-A beta antibodies systemically, there is a redistribution of the amyloid from the parenchyma to vascular elements. This increase in congophilic angiopathy is associated with increased risk of microhemorrhage. Thus, although we favor continued testing of the immunotherapy to treat Alzheimer's disease, we believe caution should be taken to minimize the risk of vascular leakage.
阿尔茨海默病是一个严重的健康问题，可用的医学治疗选择有限。免疫疗法是一种有可能减缓或逆转疾病进程的方法。在淀粉样蛋白沉积的转基因小鼠模型中，抗β淀粉样蛋白免疫疗法在减轻淀粉样蛋白负担和逆转这些小鼠中存在的记忆缺陷表型方面非常有效。已提出抗体作用的三种不同机制来介导抗β淀粉样蛋白免疫疗法的这些益处。第一种是由贝卡·所罗门及其同事提出的β淀粉样蛋白原纤维的催化溶解。第二种机制是由戴尔·申克和伊兰研究小组提出的抗体对淀粉样蛋白的调理作用以及随后巨噬细胞的吞噬作用。德马托斯、霍尔茨曼及其同事提出的第三种机制是外周汇假说，认为循环抗体隔离β淀粉样蛋白，有利于β淀粉样蛋白从中枢神经系统流出而不是流入中枢神经系统。这些机制并非相互排斥。我们的研究小组通过颅内注射和全身给予抗β淀粉样蛋白抗体评估了这些机制。我们发现了支持所有三种机制的证据，并表明它们可能协同作用以实现免疫治疗方法的显著效果。然而，在全身给予抗β淀粉样蛋白抗体的老年淀粉样前体蛋白转基因小鼠中，淀粉样蛋白从实质重新分布到血管成分。这种嗜刚果红血管病的增加与微出血风险增加有关。因此，尽管我们赞成继续测试免疫疗法来治疗阿尔茨海默病，但我们认为应谨慎行事以尽量降低血管渗漏的风险。
