小鼠中Nrf2降解毒素的功能对阿兹海默氏病的成因的可能影响

Patients carrying “Dutch” type mutation on beta-amyloid42 (E22Q, hD-Ab42) will develop early-onset Alzheimer’s disease (AD), accompanied by dramatic decrease of Nrf2 expression in hippocampal neurons. In mice, production of hD-Ab42 under intrinsic promoter of mouse beta-amyloid precursor protein did not lead to pathogenesis of AD. Previous studies have indicated that detoxification effect of Nrf2 could protect brain or neurons from damages caused by neuro-toxic Ab42 oligomers both in vivo and in vitro. The relatively constant expression level of Nrf2 in mouse brain could have helped mouse to resist toxic Ab42 oligomers in our previous studies. To test this hypothesis, Nrf2 was ablated in mice that intrinsically produce hD-Ab42, and the resulted will then be subjects of a series of analysis including behavior test and in vitro examination of expression, processing, neuro-toxicity, and clearance of hD-Ab42 in brain, in order to identify eventual involvement of Nrf2 in the pathogenesis of AD. We hope that this study may help us to further broaden and deepen our understanding on the roles of Nrf2 in AD brain and the distinct cellular protection mechanism in mice against a wide variety of stress and toxicifation, and to explore feasible strategy to promote translational medicine from mice to human and efficiency of R&D of drugs in the future.

人类Abeta42上的“荷兰式”基因突变（E22Q，hD-Ab42）会导致患者形成阿兹海默氏病（Alzheimer's disease, AD）。然而内源性表达hD-Ab42并不能导致小鼠出现明显AD症状。Nrf2已被证明对因Ab42齐聚物（oligomers）的神经毒性而造成的神经细胞的损伤有明显的保护作用，并且AD患者伴随着海马区神经元细胞中Nrf2表达的急剧减少。由此推断正是小鼠体内Nrf2水平的相对稳定导致了小鼠对突变Ab42的敏感性不同于人类。为验证这一假设，内源性表达hD-Ab42的小鼠中Nrf2被敲除，其影响也将通过对小鼠的行为测试以及一系列的对hD-Ab42的生成、神经毒性和其清除机制的全面测试来评估，鉴定小鼠中Nrf2所参与的细胞保护机制对AD成因的可能影响，以及小鼠中Nrf2所参与的细胞保护机制的特异性，为未来进一步的研究和提高转化医学和药物研发的效率积累理论基础。

小鼠内源性表达导致人类形成阿兹海默病（Alzheimer's disease, AD）的携带“荷兰式”基因突变（E22Q）的Abeta42（hD-Ab42）并不能导致该AD小鼠出现明显的AD症状。本课题推断AD小鼠体内核转录因子Nrf2水平的相对稳定导致了AD小鼠对hD-Ab42的敏感性不同于人类。为验证这一假设，AD小鼠体内Nrf2被敲除（NK-AD小鼠）。初步结果显示，12月龄的NK-AD小鼠在行为学测试上并未表现出明显的AD症状，对小鼠脑组织的分析也未发现Nrf2的敲除对AD小鼠体内hD-Ab42的积累、神经毒性和其清除机制与对照小鼠具有明显的差异。上述阴性结果正在归纳和整理中，按本课题设计初始的要求，上述阴性研究结果也将努力发表。.　　同时，我们推测可能12月龄的NK小鼠还不足以获得AD的表型，我们将继续培养NK-AD小鼠，未来在更老龄的NK-AD小鼠中继续评估Nrf2的敲除对小鼠AD的发生、发展的影响。