Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
Nature. 2011 Jan 6;469(7328):47-52. doi: 10.1038/nature09635. Epub 2010 Nov 28.
Amyloid-β oligomers may cause cognitive deficits in Alzheimer's disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer's disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer's disease.
淀粉样β寡聚体可能通过损害神经元 NMDA 型谷氨酸受体导致阿尔茨海默病的认知缺陷，而 NMDA 型谷氨酸受体的功能受受体酪氨酸激酶 EphB2 调节。在这里，我们发现淀粉样β寡聚体与 EphB2 的纤连蛋白重复结构域结合，并在蛋白酶体中触发 EphB2 的降解。为了确定 EphB2 在阿尔茨海默病和相关模型中的缺失的致病重要性，我们使用慢病毒构建体来降低或增加小鼠大脑记忆中心的 EphB2 神经元表达。在非转基因小鼠中，短发夹 RNA 介导的 EphB2 敲低降低了齿状回中的 NMDA 受体电流，并损害了长时程增强作用，这对记忆形成很重要。在人淀粉样前体蛋白转基因小鼠的齿状回中增加 EphB2 的表达逆转了 NMDA 受体依赖性长时程增强作用和记忆损伤的缺陷。因此，EphB2 的缺失在淀粉样β诱导的神经元功能障碍中是至关重要的。增加 EphB2 的水平或功能可能对阿尔茨海默病有益。
