Muhammad Alim, Flores Ingrid, Zhang Hong, Yu Rui, Staniszewski Agnieszka, Planel Emmanuel, Herman Mathieu, Ho Lingling, Kreber Robert, Honig Lawrence S, Ganetzky Barry, Duff Karen, Arancio Ottavio, Small Scott A
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7327-32. doi: 10.1073/pnas.0802545105. Epub 2008 May 14.
Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.
尽管逆向转运蛋白分选途径的缺陷已与晚发性阿尔茨海默病相关联，但这些缺陷是否为该疾病的病因仍不清楚。在这里，我们对两种基因改造动物模型进行了特征分析，以测试关于逆向转运蛋白缺陷对大脑影响的两个虽独立但相关的问题。首先，为检测认知缺陷，我们研究了逆向转运蛋白缺陷小鼠，发现它们出现了海马体依赖性记忆和突触功能障碍，这与内源性淀粉样β肽水平升高有关。其次，为检测神经退行性变和淀粉样蛋白沉积，我们研究了表达人类野生型淀粉样前体蛋白（APP）和人类β位点APP裂解酶（BACE）的逆向转运蛋白缺陷果蝇，发现它们出现了神经元丢失和人类淀粉样β聚集体。通过再现该疾病的特征，这些动物模型表明，在晚发性阿尔茨海默病中观察到的逆向转运蛋白缺陷可能促成疾病的发病机制。
