Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo.
Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo.
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发表时间：
2005
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影响因子：
82.9
通讯作者：
I. Klyubin;D. Walsh;C. Lemere;W. K. Cullen;G. Shankar;V. Betts;E. Spooner;Liying Jiang;R. Anwyl;D. Selkoe;M. Rowan
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作者：
I. Klyubin;D. Walsh;C. Lemere;W. K. Cullen;G. Shankar;V. Betts;E. Spooner;Liying Jiang;R. Anwyl;D. Selkoe;M. Rowan
针对阿尔茨海默病的实验性疾病改善治疗的最先进的临床形式之一是针对淀粉样蛋白（Abeta）的免疫接种，但这如何预防认知障碍尚不清楚。我们假设Abeta抗体可以通过直接中和大脑中潜在的突触毒性可溶性Abeta物种来发挥有益的作用。脑室内注射天然分泌的人Abeta可抑制大鼠海马体内与学习和记忆相关的长期增强（LTP），但在Abeta后注射Abeta单克隆抗体可完全阻止LTP的抑制。大小分级表明，抑制LTP的是Abeta低聚物，而不是单体或原纤维，而且Abeta抗体再次阻止了这种抑制。针对Abeta的主动免疫是部分有效的，其效果与Abeta低聚物抗体水平呈正相关。外源性和内源性抗体能够快速中和体内破坏突触可塑性的可溶性Abeta寡聚物，这表明用这种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 (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.