Inhibition of BACE1 in amyloidosis mouse

描述(由申请人提供)： 阿尔茨海默病(AD)病理的特征之一是在受影响的人的大脑中存在神经性斑块。这些斑块由细胞外沉积的淀粉样β蛋白(Abeta)组成，周围环绕着营养不良的神经突起、反应性星形胶质细胞和小胶质细胞。Abeta多肽是由人类淀粉样前体蛋白(APP)通过两种分泌酶--β位点APP裂解酶1(BACE1)和伽马(一种蛋白质复合体)的活性而产生的，这两种酶依次裂解前体。这一建议建立在一个耐人寻味的观察结果之上，即神经元中主要的β分泌酶BACE1的缺失完全阻止了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BACE1的活性，Abeta介导的病理可逆吗？这一建议验证了这样的假设，即抑制BACE1的表达将改善该小鼠模型中Abeta介导的病理的发展和演变。拟议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BACE1(AIM1)和诱导BACE1敲除(AIM2)。这些研究将为BACE1作为AD的治疗靶点提供重要的验证。

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.