Inflammation and plaque formation downstream of disrupted autophagy in Alzheimer's disease

阿尔茨海默病中自噬破坏下游的炎症和斑块形成

基本信息

批准号：
10723040
负责人：
Juliet Goldsmith
金额：
$ 8.73万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723040
关键词：
Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Precursor Autophagocytosis Autophagosome Award Biochemical Brain Cell Communication Cell model Cells Chronic Coculture Techniques Communication Complement Complex Data Deposition Diagnosis Diagnostic Disease Disease Progression Drug Design Drug Targeting Dynein ATPase Early identification Endoplasmic Reticulum Foundations Genetic Health Homeostasis Immune Impairment In Vitro Induced pluripotent stem cell derived neurons Inflammation Inflammatory Intervention Maintenance Microglia Microtubules Mitochondria Mitochondrial DNA Modeling Molecular Molecular Biology Mutation Nerve Degeneration Neurofibrillary Tangles Neurons Organelles Pathway interactions Patients Phase Phenotype Postdoctoral Fellow Process Protein Secretion Proteins Reproducibility Research Risk Risk Factors Role Sampling Societies Stress Supporting Cell Synapses System Techniques Variant Work apolipoprotein E-4 brain cell cell type cost early detection biomarkers experimental study glial activation high resolution imaging improved induced pluripotent stem cell innovation neuroinflammation neuron loss new therapeutic target novel marker pharmacologic prevent rational design risk variant stressor tau Proteins tau aggregation tau mutation therapeutic target trafficking

项目摘要

Alzheimer’s disease and related dementias (AD/ADRD) are devastating diseases to those diagnosed and come with a high cost to society. Reliable early identification and improved intervention is vital to treat patients before neuronal loss is irreversible. Autophagy is strongly implicated in the progression of AD, and thus has been an attractive therapeutic target for many years, but to reach a successful autophagy-targeting drug requires better understanding of the molecular consequences of disrupted autophagy. I propose to investigate how disrupted autophagy contributes to the chronic inflammation and plaque formation associated with the progression of AD. Using two of the most common AD risk variants as models to disrupt specific aspects of autophagy, I will investigate how the misregulation of mitochondrial DNA (mtDNA) and amyloid precursor protein (APP), autophagy cargos I identified in my postdoc, contribute to neuroinflammation, synapse loss, and plaque deposition observed in AD. AD initiation and progression involves multiple cell types, therefore I will use innovative iPSC models and cutting-edge techniques to model and manipulate complex interactions between neurons and microglia in a simplified system. In the K99 phase of this award, I will confirm that the ApoE4 AD risk variant disrupts mitochondria-endoplasmic reticulum contacts, which I predict will impair the clearance of mtDNA. I expect accumulation of mtDNA will sensitize neurons to release inflammatory factors, resulting in sustained microglia activation, release of complement and synapse loss. In the R00 phase, I will apply similar approaches mastered in the K99 phase to investigate the contribution of autophagy to plaque deposition. First, based off preliminary data, I will determine whether APP is an autophagy cargo in neurons or microglia, and whether it is normally transferred between the cell types. Second, as dysregulated Tau is a major disruptor of microtubules and organelle trafficking, I will investigate the sensitivity of TauR317W neurons to disruptions to autophagosome trafficking. I have found in my postdoctoral work that impaired autophagosome trafficking decreases degradation and increases secretion of autophagy cargo, thus I expect TauR317W sensitizes neurons to increase secretion and transfer of APP to microglia. I will then investigate the role of microglial autophagy to prevent plaque formation, and how this may be perturbed by the accumulation of Tau aggregrates and neurofibrillary tangles in TauR317W microglia. Completion of the independent aims will highlight the multifaceted role of autophagy in disease progression, identify specific molecular consequences of disrupted autophagy, and ultimately help to identify novel biomarkers and therapeutic targets for AD/ADRD.

阿尔茨海默氏病和相关痴呆症 (AD/ADRD) 对于诊断和治疗的人来说是毁灭性的疾病可靠的早期识别和改进的干预对于治疗患者至关重要。在神经元损失不可逆转之前，自噬与 AD 的进展密切相关，因此具有不可逆性。多年来一直是一个有吸引力的治疗靶点，但要获得成功的自噬靶向药物需要更好地了解自噬破坏的分子后果，我建议进行研究。自噬被破坏如何导致与自噬相关的慢性炎症和斑块形成使用两种最常见的 AD 风险变异作为模型来破坏 AD 的特定方面自噬，我将研究线粒体 DNA (mtDNA) 和淀粉样蛋白前体的失调是如何发生的蛋白质（APP），我在博士后发现的自噬货物，会导致神经炎症、突触损失和 AD 中观察到的斑块沉积涉及多种细胞类型，因此我将使用创新的 iPSC 模型和尖端技术来建模和操纵之间的复杂相互作用在这个奖项的 K99 阶段，我将确认 ApoE4 AD 的简化系统中的神经元和小胶质细胞。风险变异会破坏线粒体与内质网的接触，我预测这会损害线粒体的清除我预计线粒体DNA的积累将使神经元敏感地释放炎症因子，从而导致在R00阶段，我将应用类似的小胶质细胞持续激活、补体释放和突触损失。 K99 阶段掌握的方法来研究自噬对斑块沉积的贡献。根据初步数据，我将确定APP是否是神经元或小胶质细胞中的自噬货物，以及其次，Tau 蛋白的失调是 Tau 蛋白的主要破坏者。微管和细胞器运输，我将研究 TauR317W 神经元对破坏的敏感性我在博士后工作中发现自噬体贩运受到损害。减少降解并增加自噬货物的分泌，因此我预计 TauR317W 会使神经元变得敏感增加 APP 的分泌和转移到小胶质细胞，然后我将研究小胶质细胞自噬的作用。防止斑块形成，以及 Tau 聚集体的积累如何干扰斑块形成，以及 TauR317W 小胶质细胞中的神经原纤维缠结的独立目标的完成将突出多方面的。自噬在疾病进展中的作用，识别自噬破坏的特定分子后果，并最终帮助识别 AD/ADRD 的新型生物标志物和治疗靶点。