SYNAPTIC ABNORMALITIES IN PERFORANT PATH & BACE1

随着BACE1作为β -分泌酶参与阿尔茨海默病（AD）中β -淀粉样蛋白（Abeta）肽的生成，我们开始了一系列研究，以检测这种跨膜天冬氨酸蛋白酶的功能作用。我们证明BACE1是神经元中主要的β -分泌酶，并且它是切割APP以在大脑中产生β所必需的。此外，我们提供了强有力的证据来支持我们的假设，即BACE1和BACE2以及APP是大脑对β淀粉样变性选择性易感性的关键决定因素。显著的是，APPswe中BACE1的缺失；PS1deltaE9小鼠可以防止Abeta沉积和年龄相关的认知异常，这些异常发生在这种Abeta淀粉样变性模型中。综上所述，这些结果表明抑制BACE1可以有效减少AD患者的β负担。总体目标是严格评估BACE1作为AD的优先治疗靶点，特别关注abeta诱导异常的可逆性和大脑的修复能力。在Aim 1中，我们将通过超微结构、免疫细胞化学和生化方法，使用不同BACE1基因剂量的appswee - deltae9小鼠，研究BACE1在穿孔通路中假设的Abeta相关突触异常进化中的作用。然后，我们将在Aim 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，其中BACE1的表达可以通过

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.