The Role of Cathepsin B and Cystatin C in Alzheimer's Disease

组织蛋白酶 B 和胱抑素 C 在阿尔茨海默病中的作用

基本信息

批准号：
8431392
负责人：
Li Gan
金额：
$ 35.13万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431392
关键词：
Abbreviations Ablation Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Behavioral Binding Brain C-terminal CSF1 gene Calcium/calmodulin-dependent protein kinase Catabolism Cathepsin L Cathepsins B Cell membrane Cerebrospinal Fluid Clathrin Complement Cysteine Protease Deposition Disease Endocytosis Endocytosis Inhibition Endopeptidases Endoplasmic Reticulum Endosomes Enzyme-Linked Immunosorbent Assay Enzymes Fluorescence Foundations Genes Health Human In Vitro Indiana Insulinase Long-Term Potentiation Macrophage Colony-Stimulating Factor Masks Mediating Membrane Metalloproteases Microglia Molecular Multivesicular Body Mus Mutation N-Methylaspartate Neprilysin Neuron-Specific Enolase Neurons Nicotinic Receptors Organelles Output Pathway interactions Play Process Proteins Role Site Source Subcellular Fractions Subfamily lentivirinae Surface Synapses Synaptic Potentials Testing Therapeutic Intervention Transgenic Organisms Western Blotting Work aged behavior measurement behavior test beta amyloid pathology calmodulin-dependent protein kinase II citrate carrier complement pathway dentate gyrus design early onset endothelin-converting enzyme enolase extracellular familial Alzheimer disease in vivo inhibitor/antagonist insight morris water maze mutant neurophysiology novel therapeutics overexpression pathogen post gamma-globulins presenilin-1 presynaptic promoter receptor small hairpin RNA synaptic function therapeutic development uptake

项目摘要

DESCRIPTION (provided by applicant): Amyloid beta (Abeta), a key pathogenic factor in Alzheimer's disease (AD), accumulates and forms toxic oligomers in the brain as a result of overproduction or inefficient clearance. Thus, pathways regulating Abeta degradation and clearance are prime candidates for therapeutic intervention. We discovered that cathepsin B (CatB), a cysteine protease, degrades Abeta in vitro and in vivo. In more recent studies, we showed that the Abeta -degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC), and that reducing CysC enhances CatB- induced Abeta degradation and protects against Abeta -associated synaptic and behavioral deficits. However, unlike some other Abeta degradation enzymes, such as neprilysin (NEP, an endopeptidase with optimal activity at a neutral pH), CatB truncates Abeta at the C-terminus with optimal activity at acidic pHs. CatB also appears to be more effective than NEP in reducing higher orders of Abeta assemblies in vivo. These observations suggest that CatB and NEP may play complementary roles in Abeta degradation. The objectives of this proposal are to determine the cellular mechanisms of the CatB-CysC axis and how it and NEP might work together to regulate Abeta degradation. In Specific Aim 1, we will assess the effects of the neuronal CatB-CysC axis on Abeta degradation and neuronal synaptic function in vivo. The effects of microglia- and neuron-derived CatB will be compared. In Specific Aim 2, we will determine if neuronal CatB-CysC axis acts in the endosomal-lysosomal pathway to regulate Abeta degradation. Understanding the subcellular mechanisms of CatB-CysC axis is a prerequisite for the development of therapeutic strategies that target this newly identified pathway. In Specific Aim 3, we will examine the role of NEP in CatB-induced Abeta degradation and the role of CatB in NEP-induced Abeta degradation. By defining the interplay between the CatB-CysC axis and NEP, new insights into molecular mechanisms regulating Abeta -degradation will likely emerge. Confirmation that the CatB-CysC axis action acts in a complementary manner with NEP would lay the foundation for designing effective Abeta clearance strategies.

描述（由申请人提供）：淀粉样蛋白β（ABETA），这是阿尔茨海默氏病（AD）的关键致病因素（AD），由于过量产生或效率低下而在大脑中积累并形成有毒的低聚物。因此，调节Abeta降解和清除的途径是治疗干预的主要候选者。我们发现caltepsin b（CatB）是半胱氨酸蛋白酶，在体外和体内降解了Abeta。在最近的研究中，我们表明CATB的ABETA降解活性受到其内源性抑制剂Cystatin C（CysC）的抑制，并且减少CYSC会增强CATB诱导的ABETA降解，并防止Abeta相关的突触和行为缺陷。但是，与其他一些ABETA降解酶不同，例如NEPRILYSIN（NEP，一种具有最佳活性在中性pH值的内肽酶）不同，CATB在C-terminus上截断了在酸性pHS上具有最佳活性的C-末端。 CATB似乎也比NEP更有效地减少了体内较高的ABETA组件。这些观察结果表明，CATB和NEP可能在Abeta降解中起互补的作用。该提案的目标是确定CATB-CYSC轴的细胞机制，以及它和NEP如何共同调节Abeta降解。在特定目标1中，我们将评估神经元CATB-CYSC轴对体内Abeta降解和神经元突触功能的影响。将比较小胶质细胞和神经元衍生的CATB的影响。在特定的目标2中，我们将确定神经元CATB-CYSC轴是否在内体 - 溶菌体途径中起作用以调节Abeta降解。了解CATB-CYSC轴的亚细胞机制是开发针对这种新识别途径的治疗策略的先决条件。在特定的目标3中，我们将研究NEP在CATB诱导的ABETA降解中的作用以及CATB在NEP诱导的ABETA降解中的作用。通过定义CATB -CYSC轴与NEP之间的相互作用，可能会出现对调节Abeta-降解的分子机制的新见解。确认CATB-CYSC轴的作用与NEP的互补方式起作用将为设计有效的ABETA清除策略奠定基础。