Inhibition of BACE1 in amyloidosis mouse

描述（由申请人提供）： 阿尔茨海默病（AD）病理学的标志之一是在受影响个体的脑中存在神经炎斑块。这些斑块由淀粉样β肽（Abeta）的细胞外沉积物组成，所述淀粉样β肽（Abeta）被营养不良的神经突、反应性星形胶质细胞和小胶质细胞包围。A β肽通过两种分泌酶β位点APP裂解酶1（BACE 1）和γ（一种蛋白质复合物）的活性衍生自人淀粉样前体蛋白（APP），这两种酶依次裂解前体。这一建议是建立在一个有趣的观察基础上的，即删除BACE 1，神经元中的主要β分泌酶，完全阻止了Abeta淀粉样变性小鼠模型中的Abeta沉积。然而，一个关键的问题仍然存在：通过抑制BACE 1的活性，Abeta介导的病理是可逆的吗？该提议检验了抑制BACE 1表达将改善该小鼠模型中Abeta介导的病理学的发展和演变的假设。提出的研究旨在通过两种不同的实验方法来验证这一假设：RNA干扰（RNAi）沉默BACE 1（AIM 1）;和诱导敲除BACE 1（AIM 2）。这些研究将提供BACE 1作为AD治疗靶点的重要验证。

DESCRIPTION (provided by applicant): One of the hallmarks of Alzheimer's Disease (AD) pathology is the presence of neuritic plaques in the brains of affected individuals. These plaques are made up of extracellular deposits of amyloid beta peptide (Abeta) surrounded by dystrophic neurites, reactive astrocytes, and microglia. The Abeta peptide is derived from the human amyloid precursor protein (APP) by the activities of two secretases, beta-site APP cleaving enzyme 1 (BACE1) and gamma (a complex of proteins), which sequentially cleave the precursor. This proposal is built upon the intriguing observation that deletion of BACE1, the principal beta secretase in neurons, completely prevents Abeta deposition in a mouse model of Abeta amyloidosis. A critical question, however, remains: Is Abeta-mediated pathology reversible by inhibiting the activity of BACE1? This proposal tests the hypothesis that inhibiting BACE1 expression will ameliorate the development and evolution of Abeta-mediated pathology in this mouse model. The proposed studies are designed to test this hypothesis by two different experimental approaches: RNA interference (RNAi) to silence BACE1 (AIM 1); and inducible knock out of BACE1 (AIM 2). The studies will provide an important validation of BACE1 as a therapeutic target for AD.