Beta-amyloid Modulation: Role of BACE1/BACE2

描述(申请人提供)：阿尔茨海默病S病(AD)是一种进行性神经退行性疾病的老年人，其特征是β-淀粉样蛋白(Aβ)沉积和神经原纤维缠结在海马体和大脑皮质。淀粉样前体蛋白(APP)的内切蛋白被β-和伽马分泌酶裂解，导致产生被认为具有神经毒性的Abeta多肽。α-分泌酶对Abeta序列内APP的内切作用阻止了Abeta的形成。继BACE1和BACE2两种同源跨膜天冬氨酸蛋白酶被发现后，研究表明BACE1是β-分泌酶，而BACE2在Abeta结构域内的位置裂解以限制Abeta的分泌。最近的研究表明，BACE1可能是脑淀粉样变性的易感因子，也是治疗阿尔茨海默病的良好靶点。这项建议的总体目标是评估BACE 1/BACE2作为神经元/大脑对淀粉样变性选择性易感性的决定因素的作用，并评估BACE1作为阿尔茨海默病的高度优先治疗靶点。为了开始检验BACE1的丰富和低水平的BACE2活性是大脑中神经元对Abeta淀粉样变性选择性易感性的主要决定因素的假设，我们首先定义BACE1和BACE2在神经元/脑和非神经细胞/器官中的水平和分布；还将确定BACE1和BACE2的轴突运输。这些酶的水平/活性将在不同的细胞类型以及正常小鼠和人类、突变的APP小鼠和阿尔茨海默病尸检病例的大脑和其他器官中进行测定。其次，作为对BACE1是脑淀粉样变性的主要决定因素这一假说的直接检验，我们将确定在表达脑中BACE1水平降低或增加的转基因小鼠模型中，Abeta沉积是否能够分别得到改善或加速。最后，对于BACE1作为阿尔茨海默病治疗靶点的关键评估，BACE1和BACE2的生理作用将通过BACE1缺失、BACE2缺失和BACE1；BACE2双缺失小鼠的产生和分析来确定。这些努力的结果将提供关于为什么大脑特别容易受到淀粉样斑块沉积的重要信息，并将对设计抑制BACE1的治疗策略以努力改善阿尔茨海默病的Abeta淀粉样变性具有重要意义。

DESCRIPTION (provided by applicant): Alzheimer' s disease (AD), a progressive neurodegenerative disorder of the elderly, is characterized by the deposition of beta-amyloid (Abeta) and neurofibrillary tangles in the hippocampus and cerebral cortex. Endoproteolytic cleavages of amyloid precursor protein (APP) by beta-and gamma-secretases result in the generation of Abeta peptides that are believed to be neurotoxic. The formation of Abeta is precluded by the endoproteolytic cleavage of APP within the Abeta sequence by a-secretase. Following the discovery of two homologous transmembrane aspartyl proteases, termed BACE1 and BACE2, studies showed that BACE1 is the beta-secretase while BACE2 cleaves at sites within the Abeta domain to limit Abeta secretion. Recent studies indicated that BACE1 might be a susceptibility factor to brain amyloidosis and an excellent therapeutic target in Alzheimer's disease. The overall goals of this proposal are to assess the role of BACE 1/BACE2 as determinants of selective vulnerability of neuron/brain to amyloidosis and to evaluate BACE1 as a high priority therapeutic target in Alzheimer's disease. To begin to test the hypothesis that the abundance of BACE1 coupled to low levels of BACE2 activity is a major determinant of selective vulnerability of neurons to Abeta amyloidosis in the brain, we will first define the levels and distributions of BACE1 and BACE2 in neurons/brain and non-neural cells/organs; the axonal transport of BACE1 and BACE2 will also be determined. The levels/activities of these proteases will be determined in different cell types and the brain and other organs of normal mice and humans, mutant APP mice, and autopsied cases of Alzheimer's disease. Second, as a direct test of the hypothesis that BACE1 is a principal determinant of brain amyloidosis, we will determine whether Abeta deposition can be respectively ameliorated or accelerated in transgenic mouse models expressing reduced or increased levels of BACE1 in brain. Finally, towards the critical evaluation of BACE1 as a therapeutic target in Alzheimer's disease, the physiological roles of BACE1 and BACE2 will be determined through the generation and analysis of BACE1-null, BACE2-null, and BACE1; BACE2 double null mice. Results from these efforts will provide important information regarding why the brain is particularly susceptible to amyloid plaque deposition and will have important implications for the design of therapeutic strategy to inhibit BACE1 in efforts to ameliorate Abeta amyloidosis in Alzheimer's disease.