Sell Gabrielle L, Schaffer Thomas B, Margolis Seth S
J Clin Invest. 2017 May 1;127(5):1646-1650. doi: 10.1172/JCI85504. Epub 2017 Mar 27.
Accumulation of amyloid-β (Aβ) protein may cause synapse degeneration and cognitive impairment in Alzheimer's disease (AD) by reactivating expression of the developmental synapse repressor protein Ephexin5 (also known as ARHGEF15). Here, we have reported that Aβ is sufficient to acutely promote the production of Ephexin5 in mature hippocampal neurons and in mice expressing human amyloid precursor protein (hAPP mice), a model for familial AD that produces high brain levels of Aβ. Ephexin5 expression was highly elevated in the hippocampi of human AD patients, indicating its potential relevance to AD. We also observed elevated Ephexin5 expression in the hippocampi of hAPP mice. Removal of Ephexin5 expression eliminated hippocampal dendritic spine loss and rescued AD-associated behavioral deficits in the hAPP mice. Furthermore, selective reduction of Ephexin5 expression using shRNA in the dentate gyrus of presymptomatic adolescent hAPP mice was sufficient to protect these mice from developing cognitive impairment. Thus, pathological elevation of Ephexin5 expression critically drives Aβ-induced memory impairment, and strategies aimed at reducing Ephexin5 levels may represent an effective approach to treating AD.
淀粉样β蛋白（Aβ）的积累可能通过重新激活发育性突触抑制蛋白Ephexin5（也称为ARHGEF15）的表达，导致阿尔茨海默病（AD）中的突触退化和认知障碍。在此，我们报告Aβ足以在成熟海马神经元和表达人淀粉样前体蛋白的小鼠（hAPP小鼠，一种家族性AD模型，其大脑中Aβ水平较高）中急性促进Ephexin5的产生。Ephexin5的表达在人类AD患者的海马中显著升高，表明其与AD潜在相关。我们还观察到hAPP小鼠海马中Ephexin5表达升高。去除Ephexin5的表达消除了hAPP小鼠海马树突棘的丢失，并挽救了与AD相关的行为缺陷。此外，在症状前的青少年hAPP小鼠的齿状回中使用短发夹RNA（shRNA）选择性降低Ephexin5的表达足以保护这些小鼠不发生认知障碍。因此，Ephexin5表达的病理性升高是Aβ诱导记忆障碍的关键驱动因素，旨在降低Ephexin5水平的策略可能是治疗AD的有效方法。
