Deteriming the Role of Caspase Cleaved Tau in Alzheimer’s Disease

确定 Caspase 切割的 Tau 在阿尔茨海默病中的作用

基本信息

批准号：
10741755
负责人：
Andrew J Ambrose
金额：
$ 7.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741755
关键词：
Ablation Adverse effects Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Amyloid beta-Protein Animal Model Apoptosis Arachidonic Acids Aspartate Behavior Biological Assay Brain CASP3 gene CASP6 gene Caspase Cause of Death Cell Death Cell Death Induction Cell Line Cell model Cells Cessation of life Characteristics Chemicals Cycloheximide Development Digestion Disease Disease Progression Engineering Enzymes Event Family Genetic Goals Growth Half-Life Health Health Care Costs In Vitro Induced pluripotent stem cell derived neurons Inflammation Kinetics Knock-out Knockout Mice Knowledge Lead Length Lewy Body Dementia Measures Mus Mutation Nerve Degeneration Neurons Outcome Pathology Peptide Hydrolases Persons Pharmacologic Substance Phenotype Play Positioning Attribute Post-Translational Modification Site Predisposition Protein Isoforms Proteins Recombinant Proteins Recombinants Research Resistance Role Senile Plaques Series Site Specificity Staurosporine Stress System Tauopathies Testing Therapeutic Intervention Toxic effect Trypsin United States Up-Regulation Vesnarinone Western Blotting amyloid peptide cost design experimental study gray matter in vivo inhibitor insight liquid chromatography mass spectrometry neuroblastoma cell neuroinflammation neuron loss overexpression proteotoxicity response tau Proteins tau aggregation tau mutation tau-1 therapeutic target therapy development

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) is significant health threat that is the fastest growing top 10 cause of death in the United States. AD currently costs Americans $280 billion dollars in direct health care costs annually. AD is characterized by, among other things, fibrils of aggregated microtubule associated protein tau. Tau in these fibrils is unique in several ways including truncation by caspases. The role of caspases and cleaved tau in AD has not been clearly defined, and two non-mutually exclusive hypotheses have been proposed. The first hypothesis is that caspases are being upregulated early in AD and cleave tau to a toxic species. A second possible explanation is that caspases are overexpressed in response to tau upregulation and cleavage of tau occurs after AD progression has been initiated. The overall goal of this proposal is understanding the role caspase cleaved tau plays in tau pathology. To date, several truncated tau products have been observed in vivo, but most efforts to understand the role of these products has revolved around genetic or chemical inhibition of caspases. Among all caspases, inhibition of caspase-3 and capase-6 have shown to alleviate tau pathology and cell death in cell and animal models. Knockout of caspase-3 is lethal in mice, but caspase-6 can be knocked out of mice without any adverse effects. This begs the question, is caspases-6 a potential therapeutic target for the treatment of AD? For the answer to this question to be yes, it must be shown why blocking caspase-6 alleviates tau pathology. Our central hypothesis is that caspase cleavage of tau results in a proteotoxic species that promotes tauopathy and cell death in AD. To demonstrate this, we will first characterize where caspases can cleave tau in a recombinant system. Next, we will characterize the stability, seeding propensity, cellular half-life, and toxicity of these cleaved tau proteins. Finally, we will show that cells expressing uncleavable tau are resistant to toxicity associated with caspase induction. These experiments will demonstrate that tau cleavage is necessary for neuronal cell death induced by caspase induction. When combined with previous the observations that 1) cleaved tau correlates with AD progression and 2) blockage of caspase activity alleviates tau pathology and cell death, the proposed research will provide a strong case for caspases as therapeutic targets in AD.

项目摘要/摘要阿尔茨海默氏病（AD）是重大健康威胁，是增长最快的十大死亡原因美国。广告目前每年要花费2800亿美元的直接医疗保健费用。广告是除其他外，其特征是聚合微管相关蛋白tau的原纤维。在这些原纤维中在几种方式上是独一无二的，包括胱天蛋白酶的截断。 caspase和ofered tau在AD中的作用尚未已清楚地定义了，并提出了两个非少数排他性的假设。第一个假设是这些胱天蛋白酶在AD的早期进行了更新，并将Tau清除为有毒物种。第二个可能的解释是胱天蛋白酶响应于tau上调和tau的裂解而过表达。启动了进程。该提案的总体目标是了解胱天蛋白酶在tau病理学中裂解的作用。到日期，在体内观察到了几种截短的tau产品，但是要了解这些产品的作用的大多数努力产品围绕着胱天蛋白酶的遗传或化学抑制。在所有caspase中，抑制 caspase-3和Capase-6已证明可以减轻细胞和动物模型中的tau病理和细胞死亡。 caspase-3的敲除在小鼠中是致命的，但是caspase-6可以从小鼠中淘汰而不会产生任何不利影响。这就引出了一个问题，Caspases-6是AD治疗的潜在治疗靶点吗？为了答案这个问题是，必须显示为什么阻止caspase-6减轻tau病理学。我们的中心假设是tau的胱天蛋白酶切割导致促进的蛋白质毒性物种 AD中的Tauopathy和细胞死亡。为了证明这一点，我们将首先描述胱天蛋白酶可以清除tau的位置重组系统。接下来，我们将表征稳定性，种子倾向，细胞半衰期和毒性这些裂解的tau蛋白。最后，我们将证明表达不可泄漏的tau的细胞对毒性具有抗性与caspase诱导有关。这些实验将证明tau裂解是必要的胱天蛋白酶诱导诱导的神经元细胞死亡。当与以前的观察结果结合在一起时1）裂解的tau与AD的进展相关，2）胱天冬酶活性的阻塞减轻了Tau病理学和细胞拟议的研究将为AD中的治疗靶标提供有力的案例。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.

DOI：
10.1021/jacs.2c12240
发表时间：
2023-05-10
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Horn, Kurt S. Van;Wang, Dongju;Medina-Cleghorn, Daniel;Lee, Peter S.;Bryant, Clifford;Altobelli, Chad;Jaishankar, Priyadarshini;Ng, Raymond A.;Ambrose, Andrew J.;Tang, Yinyan;Renslo, Adam R.;Arkin, Michelle R.;Leung, Kevin K.
通讯作者：
Leung, Kevin K.