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）：神经退行性疾病中 tau 病理学的机制尚未完全阐明，然而，越来越多的证据表明，除磷酸化外，tau 翻译后修饰可能在这些机制中发挥重要作用。已表明此类修饰之一是钙蛋白酶介导的 tau 裂解，这种裂解导致 17 kDa tau45-230 片段的生成。此外，我们的数据表明，该片段会导致离线培养的海马神经元进行性退化，而阻止该片段生成的条件与中枢神经元的神经元存活率增强有关。在表达 tau45-230 的转基因小鼠中检测到神经元死亡、突触损失和行为异常增加，这些数据提供了证据表明 tau 裂解成这种神经毒性片段是一种潜在的危险因素。另一方面，tau45-230 诱导变性和细胞死亡的机制仍不清楚。根据我们的初步结果，我们发现 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 蛋白的聚集，从而诱导形成更小、毒性更大的聚集体；2) tau45-230 可能以单体或小聚集体的形式干扰全长 tau 的生物学功能。为了检验这些假设，我们建议：1) 评估从 AD 获得的脑样本中 tau45-230 聚集体的存在和毒性。和其他 tau 蛋白病受试者；2) 确定 tau45-230 在多大程度上调节全长 tau 聚集；以及 3) 确定其机制tau45-230 改变中枢神经元中的 tau 功能。这些实验将通过多种技术进行，包括：蛋白质印迹分析、免疫细胞化学、体外聚合测定、聚集体纯化、同源重组技术、微管结合测定、活细胞显微镜检查。和细胞活力测定可以确定一种新的变性分子途径，此外，它们还可以为诊断、预防和最终的治疗提供有用的信息。 AD 和其他 tau 病。