Tau oligomer conformers and synaptic vulnerability/resilience in AD and related disorders

AD 及相关疾病中的 Tau 寡聚体构象异构体和突触脆弱性/弹性

• 批准号: 10271855
• 负责人: Agenor Limon
• 金额: $ 78.99万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271855
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease therapy; American; Autologous; Automobile Driving; Binding; Biochemistry; Brain; Caring; Clinical; Clinical Treatment; Consensus; Data; Dementia; Development; Disease; Effectiveness; Event; Fluorescence; Fostering; Foundations; Functional disorder; Goals; Health; Health Care Costs; Human; Individual; Knowledge; LDL-Receptor Related Protein 1; Lipoprotein Receptor; Literature; Long-Term Potentiation; Mediating; Mind; Mission; Molecular; Molecular Neurobiology; Pathologic; Pathology; Patients; Physiology; Preventive; Proteins; Public Health; Publishing; Research; Resistance; Role; Severities; Specimen; Staging; Standardization; Suggestion; Synapses; Synaptic Receptors; Tauopathies; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Vertebral column; Work; base; conformer; curative treatments; glutamatergic signaling; improved; innovation; neuron loss; neuropathology; non-demented; novel; protein complex; receptor mediated endocytosis; resilience; response; societal costs; sound; synaptic function; tau Proteins; tau aggregation; tau interaction; uptake

PROJECT SUMMARY/ABSTRACT Finding a resolving cure for Alzheimer's Disease (AD) is an urgent critical need and there is ample consensus that successful treatments should target early disease events. Among these, synaptic dysfunction induced by soluble oligomers of tau (TauO) is recognized as one of the earliest key events in AD and related disorders, where disease-specific TauO conformers (strains) may drive the diverse clinical presentations. Thus, blocking synaptic demise induced by TauO conformers is a highly desirable therapeutic strategy, its potential effectiveness supported by the existence of resilient individuals who remain Non-Demented despite the CNS presence of late-stage Braak AD Neuropathology (here termed NDAN) that present with functional synapses devoid of TauO. Notably, late Braak stage pathology paralleled by intact synapses in NDAN suggests the novel concept that trans-synaptic spreading of tau and tau-driven synaptic toxicity are two distinct phenomena that coexist in AD and other symptomatic tauopathies but not in NDAN, where the toxic impact of TauO on synapses (but not spreading) is curbed. While such evidence indicates that rejecting synaptic tau toxic impact as a protective mechanism can be effectively enabled in the human brain despite the spread of AD neuropathology, a therapeutic strategy to achieve such a game-changing goal remains missing. Filling this critical knowledge gap by laying the molecular foundations for the development of such therapeutic strategy is the overall objective of the present project. Our central hypothesis is that dysfunctional engagement of synapses by TauO is determined by the type of tau strain and its binding to LRP1 (a synaptic receptor essential for tau uptake and spreading), which differentially affects LRP1-containing protein complexes in vulnerable vs. resilient synapses. We will test our central hypothesis by evaluating binding dynamic and functional impact of disease-specific brain-derived TauO conformers on human synapses as a function of LRP1-mediated toxicity (Aim 1) and by evaluating the functional response of human synapses from different tauopathies (AD, PSP) and resilience status (NDAN, PART) to TauO as a function of the synaptic LRP1 (Aim 2). At the completion of the proposed studies, we expect to have documented a previously unappreciated mechanism of synaptic interaction of TauO conformers as well as a phenomenon of synaptic resistance modulated by LRP1. This discovery will have a significant impact in the development of an innovative treatment concept for AD centered on sustaining synaptic resistance to toxic oligomers, a strategy expected effective as demonstrated by NDAN subjects. A uniquely qualified investigative team has been assembled to successfully accomplish this project, bringing together expertise in AD molecular neurobiology (Taglialatela), human synaptic physiology (Limon) and function (Krishnan) and biochemistry of tau oligomers (Kayed).

项目总结/摘要 寻找阿尔茨海默病（AD）的解决方法是一个紧迫的关键需求，并且有充分的共识 成功的治疗应该针对早期疾病事件。其中，突触功能障碍由 可溶性tau寡聚体（TauO）被认为是AD和相关疾病中最早的关键事件之一， 其中疾病特异性TauO构象异构体（菌株）可驱动不同的临床表现。因此，阻塞 由TauO构象异构体诱导的突触死亡是非常理想的治疗策略，其潜力 有效性得到了尽管存在CNS但仍保持非痴呆的弹性个体的存在的支持 存在晚期Braak AD神经病理学（此处称为NDAN），其存在功能性突触 缺乏TauO。值得注意的是，在NDAN中，由完整突触覆盖的Braak晚期病理学表明， tau的跨突触扩散和tau驱动的突触毒性是两种不同的现象， 在AD和其他有症状的tau蛋白病中共存，但在NDAN中不存在，NDAN中TauO对突触的毒性影响 (but不扩散）。虽然这些证据表明，拒绝突触tau蛋白的毒性影响， 尽管AD神经病理学扩散，但在人脑中可以有效地启用保护机制， 实现这一改变游戏规则的目标的治疗策略仍然缺失。填补这一关键的知识空白 通过为这种治疗策略的发展奠定分子基础， 目前的项目。我们的中心假设是，TauO对突触的功能障碍性参与是由 通过tau菌株的类型及其与LRP 1（tau摄取和扩散所必需的突触受体）的结合， 其在脆弱和弹性突触中对含LRP 1的蛋白复合物产生不同的影响。我们将测试 我们的中心假设是通过评估疾病特异性脑源性的结合动力学和功能影响， 作为LRP 1介导的毒性的函数的人突触上的TauO构象异构体（Aim 1），并通过评估 来自不同Tau蛋白病（AD，PSP）和弹性状态（NDAN， PART）到TauO作为突触LRP 1的函数（Aim 2）。在建议的研究完成后，我们预期 也证明了TauO构象体之间突触相互作用的一种以前未被认识的机制 作为LRP 1调节的突触阻力现象。这一发现将对世界产生重大影响。 开发一种创新的AD治疗概念，以维持突触抵抗为中心， 有毒的低聚物，一种预期有效的策略，如NDAN受试者所示。一个独一无二的 为了成功完成这一项目，已经组建了一个调查小组， AD分子神经生物学（Taglialatela）、人类突触生理学（利蒙）和功能（Krishnan）以及 tau寡聚体的生物化学（Kayed）。