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; 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).

项目摘要/摘要 寻找解决阿尔茨海默氏病（AD）的解决方法是迫切的迫切需要，并且有充分的共识 成功的治疗应针对早期疾病事件。其中，由 Tau（Tauo）的可溶性低聚物被认为是AD和相关疾病中最早的关键事件之一， 疾病特异性的TAUO构象体（菌株）可能会推动各种临床表现。因此，阻止 Tauo构象体诱导的突触灭亡是一种非常理想的治疗策略，其潜力 尽管存在中枢神经系统 具有功能性突触的后期Braak AD神经病理（此处称为NDAN）的存在 没有tauo。值得注意的是，恩丹（Ndan）完整突触平行的后期布拉克阶段病理学表明这是小说 tau和tau驱动的突触毒性的反触发性传播的概念是两个不同的现象 在AD和其他有症状的Tauopath中共存，但在Ndan中不存在，Tauo对突触的毒性影响 （但不扩散）是遏制的。尽管这种证据表明拒绝突触Tau有毒影响 尽管AD神经病理学传播，但可以在人脑中有效地实现保护机制 实现这种改变游戏的目标的治疗策略仍然缺失。填补这个关键的知识差距 通过为开发这种治疗策略的发展奠定分子基础是总体目标 本项目。我们的中心假设是确定Tauo突触的功能失调 通过Tau菌株的类型及其与LRP1的结合（一种突触受体，对Tau摄取和扩散必不可少）， 这会差异地影响易受伤害与弹性突触中含有LRP1的蛋白质复合物。我们将测试 我们的中心假设通过评估疾病特异性大脑衍生的结合动态和功能影响 tauo对人突触的构象体是LRP1介导的毒性的函数（AIM 1），并通过评估 来自不同tauopathies（AD，PSP）和弹性状态的人类突触的功能反应（ndan， 部分）到tau作为突触LRP1的函数（AIM 2）。拟议的研究完成后，我们期望 还记录了先前未批准的tauo构象体突触相互作用的机制 作为由LRP1调节的突触抗性现象。这一发现将对 开发以维持突触抗性为中心的广告创新治疗概念 有毒的低聚物，这是NDAN受试者证明的一种预期有效的策略。独特的资格 调查团队已组装成成功完成该项目，将专业知识融合在一起 AD分子神经生物学（Taglialatela），人类突触生理学（Limon）和功能（Krishnan）和 Tau低聚物的生物化学（皮划艇）。