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

阿尔茨海默氏病和相关痴呆（AD/ADRD）是对那些被诊断和治疗的人具有破坏性的疾病。 给社会带来很高的代价。可靠的早期识别和改进的干预对于治疗患者至关重要 神经元的丧失是不可逆的自噬与AD的进展密切相关，因此， 多年来一直是一个有吸引力的治疗靶点，但要达到一个成功的自噬靶向药物 需要更好地理解自噬中断的分子后果。我提议调查 自噬的破坏如何导致慢性炎症和斑块的形成， AD的进展。使用两种最常见的AD风险变体作为模型， 自噬，我将研究如何失调线粒体DNA（mtDNA）和淀粉样蛋白前体 蛋白质（APP），我在博士后研究中发现的自噬货物，有助于神经炎症，突触丢失， 在AD中观察到斑块沉积。AD的启动和进展涉及多种细胞类型，因此我将使用 创新的iPSC模型和尖端技术，以模拟和操纵复杂的相互作用， 神经元和小胶质细胞在一个简化的系统。在本奖项的K99阶段，我将确认ApoE 4 AD 风险变异破坏了内质网的接触，我预测这将损害清除 线粒体DNA我预计线粒体DNA的积累会使神经元敏感，释放炎症因子，导致 持续的小胶质细胞活化、补体释放和突触丧失。在R 00阶段，我将应用类似的 在K99阶段掌握的方法来研究自噬对斑块沉积的贡献。第一、 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， 它是否在细胞类型之间正常转移。第二，由于Tau蛋白的失调是一种主要的干扰因子， 微管和细胞器运输，我将研究TauR 317 W神经元对破坏的敏感性， 自噬体运输。我在博士后工作中发现，受损的自噬体运输 减少降解并增加自噬货物的分泌，因此我预计TauR 317 W会使神经元敏感 增加APP向小胶质细胞的分泌和转移。然后，我将研究小胶质细胞自噬的作用， 防止斑块形成，以及这可能如何被Tau聚集体的积累所干扰， TauR 317 W小胶质细胞中的神经元缠结。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，确定自噬破坏的特定分子后果， 并最终帮助识别AD/ADRD的新生物标志物和治疗靶点。

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.