Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo
Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo
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DOI：
10.1038/nm1234
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发表时间：
2005-05-01
期刊：
影响因子：
82.9
通讯作者：
Rowan, MJ
中科院分区：
文献类型：
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作者：
Klyubin, I;Walsh, DM;Rowan, MJ
阿尔茨海默病的实验性疾病修饰治疗的最先进的临床形式之一是针对淀粉样β蛋白（A β）的免疫接种（1-7），但这如何预防认知障碍尚不清楚（8-13）。我们假设A β抗体可以通过直接中和脑中潜在的突触毒性可溶性A β物质发挥有益作用（14-16）。脑室内注射天然分泌的人A β可抑制大鼠海马体内的长时程增强（LTP），这是学习和记忆的相关因素（17），但在A β后注射A β单克隆抗体可完全阻止LTP的抑制。大小分级显示，A β寡聚体，而不是单体或原纤维，负责抑制LTP，A β抗体再次阻止这种抑制。针对A β的主动免疫是部分有效的，并且效果与针对A β寡聚体的抗体水平呈正相关。外源性和内源性抗体在体内快速中和破坏突触可塑性的可溶性A β寡聚体的能力表明，用此类抗体治疗可能在早期阿尔茨海默病中显示可逆的认知缺陷。
One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (A beta)(1-7), but how this may prevent cognitive impairment is unclear(8-13). We hypothesized that antibodies to A beta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble A beta species(14-16) in the brain. Intracerebroventricular injection of naturally secreted human A beta inhibited long-term potentiation (LTP), a correlate of learning and memory(17), in rat hippocampus in vivo but a monoclonal antibody to A beta completely prevented the inhibition of LTP when injected after A beta. Size fractionation showed that A beta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an A beta antibody again prevented such inhibition. Active immunization against A beta was partially effective, and the effects correlated positively with levels of antibodies to A beta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble A beta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.