SYNAPTIC ABNORMALITIES IN PERFORANT PATH & BACE1

随着BACE1作为参与阿尔茨海默病(AD)中β-淀粉样多肽(Abeta)生成的β-分泌酶的发现，我们开始了一系列的研究，以探讨这种跨膜天冬氨酸蛋白酶的功能作用。我们证明了BACE1是神经元中主要的β-分泌酶，并且它对于切割APP在大脑中产生Abeta是必不可少的。此外，我们提供了强有力的证据支持我们的假设，即BACE1和BACE2以及APP是大脑选择性易患Aβ淀粉样变性的关键决定因素。值得注意的是，APPswe；PS1deltaE9小鼠中BACE1的缺失可以防止Abeta沉积和在这种Abeta淀粉样变性模型中发生的与年龄相关的认知异常。综上所述，这些结果提示抑制BACE1在降低AD患者的Abeta负荷方面应该是有效的。总体目标是将BACE1作为AD的高优先级治疗靶点进行批判性评估，特别是关注Abeta诱导的异常的可逆性和大脑修复的能力。在目标1中，我们将使用不同BACE1基因剂量的APPswe-deltaE9小鼠，通过超微结构、免疫细胞化学和生化方法来研究BACE1在穿支通路中假想的Abeta相关突触异常演变中的作用。然后，我们将在目标2中通过评估APPswe-PS1deltaE9小鼠来检查穿孔通路中结构和生化异常的可逆性，在APPswe-PS1deltaE9小鼠中，BACE1的表达可以通过 Tet-off转基因系统或慢病毒RNA干扰方法。我们建议的结果 研究将提供有关突触特征和进化的重要信息 通路，AP诱导的异常的可逆性，脑修复的能力 穿孔通路，以及抑制BACE1活性在改善Abeta中的价值 阿尔茨海默病的淀粉样变性。

With the discovery of BACE1 as the beta-secretase involved in the generation of beta-amyloid (Abeta) peptides in Alzheimer's disease (AD), we embarked on a series of studies to examine the functional roles of this transmembrane aspartal protease. We demonstrated that BACE1 is the principal beta-secretase in neurons and that it is essential to cleave APP to generate Abeta in the brain. Moreover, we have provided strong evidence to support our hypothesis that BACE1 and BACE2, along with APP are key determinants of selective vulnerability of brain to Abeta amyloidosis. Significantly, deletion of BACE1 in APPswe;PS1deltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. In concert, these results suggest that inhibition of BACE1 should be effective in reducing the Abeta burden in AD. The overall goal is to evaluate critically BACE1 as a high priority therapeutic target for AD, particularly focusing on the reversibility of Abeta-induced abnormalities and the capacity of the brain for repair. In Aim 1, we will examine the role of BACE1 in the evolution of hypothesized Abeta related synaptic abnormalities in the perforant pathway by ultrastructural, immunocytochemical, and biochemical methods using APPswe-deltaE9 mice with varying gene dosage of BACE1. We then will examine in Aim 2 the reversibility of the structural and biochemical abnormalities in the perforant pathway by evaluating APPswe-PS1deltaE9 mice in which expression of BACE1 can be regulated via tet-off transgenic system or by lentiviral RNA interference methods. Results from our proposed studies will provide important information regarding the character and evolution of synaptic pathways, the reversibility of Ap-induced abnormalities, the capacity of the brain for repair in the perforant pathway, and the value of inhibition of BACE1 activity in efforts to ameliorate Abeta amyloidosis in AD.