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

• 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
• 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' s Disease; Alzheimer' 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

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）正在毁灭诊断患者的疾病 对社会的成本高昂，并改善干预措施至关重要 在神经元丧失是不可逆的之前。 多年来一直是有吸引力的治疗靶点，但要达到靶向自噬药物 需要更好地了解破坏自噬的分子后果。 自噬如何有助于与之相关的慢性炎症和斑块形成 最常见的广告风险变体的进展 自噬，我将调查米孔drial DNA（mtDNA）和淀粉样蛋白前体的正调 蛋白质（APP），在我的博士后确定的自噬货物，有助于神经炎症，突触丧失，并且 在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，以建模和操纵复杂的相互作用 在简化系统中的神经元和小胶质细胞。 风险变体mitchondria-端质网触点，我预测这将损害清除 mtdna。 持续的小胶质细胞激活，补体的释放和突触损失。 在K99阶段掌握的方法研究自噬对牙菌斑沉积的贡献。 根据初步数据，我将确定应用程序是否是神经元或小胶质细胞和小胶质细胞的自噬货物。 它通常是在细胞类型之间转移的。 微管和细胞器贩运，我将调查Tour317W神经元对中断的敏感性 自噬体贩运。 降低降解并增加自噬货物的秘密，因此我希望Taur317W敏感神经元 增加应用程序向小胶质细胞的秘密和转移。 防止牙菌斑形成，以及如何通过tau诱导的积累来扰动这一点 Taur317W小胶质细胞中的神经原纤维缠结。 自噬在疾病进展中的作用，确定自噬中断的特定分子后果， 并最终有助于确定Novy Novy Nove Notho viomarkers和治疗目标忘记了AD/ADRD。