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

阿尔茨海默病和相关痴呆症(AD/ADRD)是一种对那些被诊断和 随之而来的是社会的高昂成本。可靠的早期识别和改进的干预对患者的治疗至关重要 在神经元丧失之前是不可逆转的。自噬与阿尔茨海默病的进展密切相关，因此 多年来一直是一个有吸引力的治疗靶点，但为了获得成功的自噬靶向药物 需要更好地理解被破坏的自噬的分子后果。我提议调查一下 被破坏的自噬如何促进慢性炎症和斑块的形成 AD的进展。使用两个最常见的AD风险变量作为模型，以扰乱 自噬，我将调查线粒体DNA(MtDNA)和淀粉样前体的错误调控 蛋白质(APP)，我在博士后发现的自噬货物，会导致神经炎症、突触丢失和 在AD中观察到斑块沉积。广告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，用于建模和处理 简化系统中的神经元和小胶质细胞。在这个奖项的K99阶段，我将确认ApoE4 AD 风险变异破坏了线粒体-内质网的联系，我预测这将损害对 线粒体DNA。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 持续的小胶质细胞激活、补体释放和突触丢失。在R00阶段，我将应用类似的 在K99期掌握的方法，以调查自噬对斑块沉积的贡献。第一, 根据初步数据，我将确定APP是神经元还是小胶质细胞的自噬货物，以及 它是否正常地在细胞类型之间转移。第二，由于不受监管的Tau是一个主要的破坏者 微管和细胞器运输，我将研究TauR317W神经元对干扰的敏感性 自噬体运货。我在我的博士后研究中发现，损害了自噬体运货 减少降解并增加自噬货物的分泌，因此我预计TauR317W会使神经元敏感 增加APP向小胶质细胞的分泌和转运。然后我将研究小胶质细胞自噬在 防止斑块形成，以及这可能如何被Tau聚集体和Tau聚集体的积累干扰 TauR317W小胶质细胞内神经原纤维缠绕。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，确定中断的自噬的特定分子后果， 并最终帮助确定AD/ADRD的新生物标记物和治疗靶点。

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.