Beta-amyloid Modulation: Role of BACE1/BACE2

描述（由申请人提供）：阿尔茨海默病（AD）是一种老年人进行性神经退行性疾病，其特征在于海马和大脑皮层中β-淀粉样蛋白（Abeta）和神经纤维缠结的沉积。β-和γ-分泌酶对淀粉样前体蛋白（APP）的胞内蛋白水解切割导致产生被认为具有神经毒性的Abeta肽。通过α-分泌酶对A β序列内的APP进行内切蛋白水解切割，阻止A β的形成。在发现两种同源的跨膜乙酰基蛋白酶（称为BACE 1和BACE 2）之后，研究表明BACE 1是β-分泌酶，而BACE 2在Abeta结构域内的位点切割以限制Abeta分泌。近年来的研究表明，BACE 1可能是脑淀粉样变的易感因子，也是阿尔茨海默病治疗的一个很好的靶点。该提案的总体目标是评估BACE 1/BACE 2作为神经元/脑对淀粉样变性的选择性脆弱性的决定因素的作用，并评估BACE 1作为阿尔茨海默病的高优先级治疗靶点。为了开始检验BACE 1的丰度与低水平的BACE 2活性偶联是脑中神经元对A β淀粉样变性的选择性脆弱性的主要决定因素这一假设，我们将首先确定BACE 1和BACE 2在神经元/脑和非神经细胞/器官中的水平和分布;还将确定BACE 1和BACE 2的轴突转运。这些蛋白酶的水平/活性将在正常小鼠和人、突变APP小鼠和阿尔茨海默病尸检病例的不同细胞类型和脑及其他器官中测定。第二，作为对BACE 1是脑淀粉样变性的主要决定因素这一假设的直接检验，我们将确定在脑中表达降低或增加水平的BACE 1的转基因小鼠模型中是否可以分别改善或加速Abeta沉积。最后，为了对BACE 1作为阿尔茨海默病治疗靶点的关键评价，将通过BACE 1-null、BACE 2-null和BACE 1; BACE 2双null小鼠的产生和分析来确定BACE 1和BACE 2的生理作用。这些努力的结果将提供关于为什么大脑特别容易发生淀粉样斑块沉积的重要信息，并且将对设计治疗策略以抑制BACE 1以改善阿尔茨海默病中的A β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.