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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（由申请人提供）：尚未完全阐明神经退行性疾病中tau病理学的潜在机制。然而，越来越多的证据表明，tau蛋白的翻译后修饰，而不是磷酸化，可能在这些机制中发挥重要作用。最近，我们已经表明，这样的修改之一是钙蛋白酶介导的tau蛋白裂解。这种切割导致在阿尔茨海默病（AD）和其他tau蛋白病的情况下产生17 kDa的tau 45 -230片段。此外，我们的数据表明，该片段诱导培养的海马神经元进行性变性。相反，阻止该片段产生的条件与中枢神经元中神经元存活增强相关。此外，在表达tau 45 -230的转基因小鼠中已经检测到增加的神经元死亡、突触丧失和行为异常。总之，这些数据提供的证据表明，tau蛋白裂解成这种神经毒性片段是神经变性的保守分子致病途径。另一方面，tau 45 -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tau 45 -230可以通过双重机制发挥其神经毒性作用：1）tau 45 -230可以调节全长tau的聚集，诱导形成更小和更毒性的聚集体; 2）tau 45 -230可以作为单体或小聚集体干扰全长tau的生物学功能。为了验证这些假设，我们建议：1）评估从AD和其他tau蛋白病受试者获得的脑样品中tau 45 -230聚集体的存在和毒性; 2）确定tau 45 -230在多大程度上调节全长tau蛋白聚集; 3）鉴定tau 45 -230改变中枢神经元中tau蛋白功能的机制。这些实验将通过以下技术的组合进行，包括：蛋白质印迹分析、免疫细胞化学、体外聚合试验、聚集体纯化、同源重组技术、微管结合试验、活细胞显微镜检查和细胞活力试验。这些研究可能会导致一种新的分子退化途径的鉴定。此外，它们可以为AD和其他tau蛋白病的诊断、预防和最终治疗提供有用的信息。