Mechanisms Underlying Tau45-230-Induced Neuronal Degeneration

Tau45-230 诱导的神经元变性的潜在机制

基本信息

批准号：
9762225
负责人：
ADRIANA B. FERREIRA
金额：
$ 33万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762225
关键词：
Affect Alzheimer&apos s Disease Antibodies Area Axonal Transport Behavioral Binding Biochemical Biological Assay Biological Process Brain Brain Diseases Brain region Calpain Cell Death Cell Survival Data Diagnosis Disease Electrophoresis Generations Goals Hippocampus (Brain)In Situ In Vitro Laboratories Lead Length MAPT gene Mediating Microscopy Microtubule Polymerization Microtubule Stabilization Microtubules Modification Molecular Morphology Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Pathogenicity Pathology Pathway interactions Phosphorylation Play Prevention Research Role Sampling Solubility Synapses System Tauopathies Techniques Testing Therapeutic Intervention Toxic effect Transgenic Mice Western Blotting base experimental study homologous recombination immunocytochemistry in vivo insight light scattering live cell microscopy monomer neuron loss neuronal survival neurotoxic new therapeutic target novel polymerization prevent public health relevance tau Proteins tau aggregation tau function tau phosphorylation tool

项目摘要

DESCRIPTION (provided by applicant): The mechanisms underlying tau pathology in neurodegenerative diseases have not been completely elucidated. However, a growing body of evidence suggests that tau posttranslational modifications, other than phosphorylation, might play an important role in those mechanisms. Recently, we have shown that one of such modifications is calpain-mediated tau cleavage. This cleavage leads to the generation of the 17 kDa tau45-230 fragment in the context of Alzheimer's disease (AD) and other tauopathies. In addition, our data indicated that this fragment induced progressive degeneration in cultured hippocampal neurons. Conversely, conditions that prevented the generation of this fragment were associated with enhanced neuronal survival in central neurons. Furthermore, increased neuronal death, synapse loss, and behavioral abnormalities have been detected in transgenic mice expressing tau45-230. Together, these data provide evidence indicating that tau cleavage into this neurotoxic fragment is a conserved molecular pathogenic pathway of neurodegeneration. On the other hand, the mechanisms by which tau45-230 induces degeneration and cell death remain unknown. Based on our preliminary results, we hypothesize that tau45-230 could exert its neurotoxic effects through a dual mechanism: 1) tau45-230 could modulate the aggregation of full-length tau inducing the formation of smaller and more toxic aggregates; and 2) tau45-230 could interfere, either as a monomer or as small aggregates, with full-length tau's biological functions. To test these hypotheses, we propose to: 1) assess the presence and toxicity of tau45-230 aggregates in brain samples obtained from AD and other tauopathy subjects; 2) determine to what extent tau45-230 modulates full-length tau aggregation; and 3) identify the mechanisms by which tau45-230 alters tau function in central neurons. These experiments will be performed by means of a combination of techniques including: Western blot analysis, immunocytochemistry, in vitro polymerization assays, aggregate purification, homologous recombination techniques, microtubule-binding assays, live cell microscopy, and cell viability assays. These studies could lead to the identification of a novel molecular pathway of degeneration. In addition, they could provide useful for the diagnosis, prevention, and eventually the treatment of AD and other tauopathies.

描述（由适用提供）：神经退行性疾病中TAU病理的机制尚未完全阐明。但是，越来越多的证据表明，tau翻译后修饰（除磷酸化以外）可能在这些机制中起重要作用。最近，我们已经表明，这种修饰之一是钙蛋白酶介导的tau裂解。这种裂解导致在阿尔茨海默氏病（AD）和其他tauopathies的背景下产生17 kDa tau45-230的片段。此外，我们的数据表明，该片段诱导培养的海马神经元的进行性变性。相反，阻止这种片段产生的条件与中枢神经元中神经元存活的增强有关。此外，在表达TAU45-230的转基因小鼠中发现了神经元死亡，突触丧失和行为异常。这些数据共同提供了证据，表明tau裂解到这种神经毒性片段中是神经变性的保守分子致病途径。另一方面，TAU45-230诱导变性和细胞死亡的机制仍然未知。基于我们的初步结果，我们假设TAU45-230可以通过双重机制发挥其神经毒性作用：1）TAU45-230可以调节全长TAU的聚集会诱导较小且较毒性的聚集体的形成； 2）TAU45-230可能会以全长Tau的生物学功能为单体或小骨料。为了检验这些假设，我们建议：1）评估从AD和其他tauopathy受试者获得的大脑样品中Tau45-230骨料的存在和毒性； 2）确定tau45-230在多大程度上调节全长tau聚集； 3）确定tau45-230在中央神经元中改变tau功能的机制。这些实验将通过多种技术组合进行，包括：蛋白质印迹分析，免疫细胞化学，体外聚合测定，骨料纯化，同源重组技术，微管结合测定，活细胞显微镜和细胞通过纤维效应分析。这些研究可能导致鉴定出新的变性分子途径。此外，它们可以为诊断，预防以及最终对AD和其他tauopath的治疗提供有用。