Senechal Yann, Prut Laetitia, Kelly Peter H, Staufenbiel Matthias, Natt Francois, Hoyer Daniel, Wiessner Christoph, Dev Kumlesh K
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Brain Res. 2008 Dec 3;1243:124-33. doi: 10.1016/j.brainres.2008.09.024. Epub 2008 Sep 18.
Genetic abnormalities in amyloid precursor protein (APP) are associated with Down's syndrome and familial Alzheimer's disease where hallmark plaques contain A beta peptides derived from APP. Both APP and its derivatives are implicated in neurodegenerative processes and may play important physiological and pathophysiological roles in synaptic function. Here, we show that young APP23 transgenic mice overexpressing human APP with the Swedish double mutation display altered novelty seeking behavior before the age of plaque onset. Using short interfering RNA (siRNA) targeted against APP, we investigate the direct contribution of APP and its derivatives to this behavioral deficit. After validating siRNAs targeting human APP in vitro, siRNAs were infused directly into the brain of APP23 mice for 2 weeks. Behavioral analysis shows that infusion of siRNA targeted against APP completely reverses increased exploratory activity in APP23 mice. Collectively, these data suggest that excessive APP and/or its derivatives, causes a hyperactive phenotype in APP23 mice when placed in a novel environment, which is fully reversible and not linked to plaque deposits.
淀粉样前体蛋白（APP）的基因异常与唐氏综合征和家族性阿尔茨海默病有关，在这些疾病中，标志性斑块含有源自APP的β淀粉样肽。APP及其衍生物都与神经退行性过程有关，并且可能在突触功能中发挥重要的生理和病理生理作用。在此，我们表明，过表达带有瑞典双突变的人APP的年轻APP23转基因小鼠在斑块出现之前就表现出新奇寻求行为的改变。使用针对APP的短干扰RNA（siRNA），我们研究了APP及其衍生物对这种行为缺陷的直接作用。在体外验证了靶向人APP的siRNA后，将siRNA直接注入APP23小鼠的大脑中持续2周。行为分析表明，注入针对APP的siRNA可完全逆转APP23小鼠增加的探索活动。总体而言，这些数据表明，过量的APP和/或其衍生物在置于新环境中时会导致APP23小鼠出现多动表型，这种表型是完全可逆的，且与斑块沉积无关。
