Modulation of autophagic flux as a therapeutic strategy for Alzheimer's disease

自噬是一种分解代谢的细胞循环过程，维持细胞的动态平衡，其失调 与多种疾病有牵连，包括阿尔茨海默病(AD)等神经退行性疾病。 AD是一种与年龄相关的神经退行性疾病，在美国影响着500多万人。 在AD中观察到自噬和溶酶体缺陷，包括自噬小泡的堆积 溶酶体中间体以及自噬小体内容物的有缺陷的溶酶体处理。小的- 能够克服这些缺陷的分子自噬激活剂可能会阻止疾病的进展 通过恢复细胞内稳态，防止神经细胞损伤。我们的中央 假设小分子自噬激活剂将恢复自噬和溶酶体的动态平衡 展示神经保护作用，防止疾病进展和改善阿尔茨海默氏症 活体症状。这一假设将通过该提案的总体目标进行检验，以优化 自噬激活剂作为体内工具化合物和药物先导及评价自噬效果的研究 疾病相关分析和体外神经元模型中AD表型分辨的调制 作为活体模型。我们的方法是创新的，因为我们发现了不依赖mTOR的自噬 激活剂，并将在神经元模型中识别和验证其独特的靶点和作用机制 有可能揭示AD药物发现的新靶点。这项提案的目标将有助于实现这一目标 我们的长期目标是为未得到满足的神经退行性疾病开发新的治疗方法。FDA- 已批准的治疗AD的药物可以治疗疾病的症状，但不能改善潜在的细胞损伤 导致疾病进展，进一步突出了对新的神经保护性治疗选择的需要。

Autophagy is a catabolic cellular recycling process that maintains cellular homeostasis and its dysregulation has been implicated in numerous diseases, including neurodegenerative diseases such as Alzheimer’s disease (AD). AD is an age-related neurodegenerative disease that affects more than 5 million people in the United States. Autophagic and lysosomal defects have been observed in AD, including accumulation of autophagic vesicles and lysosomal intermediates as well as defective lysosomal processing of autophagosome contents. Small- molecule autophagy activators that could overcome these defects could potentially halt disease progression through the restoration of cellular homeostasis and the prevention of neuronal cell damage. Our central hypothesis is that small-molecule autophagy activators will restore autophagic and lysosomal homeostasis and exhibit neuroprotective effects that will prevent disease progression and ameliorate Alzheimer’s disease symptoms in vivo. This hypothesis will be tested through the overall objectives of this proposal to optimize an autophagy activator as an in vivo tool compound and drug lead and to evaluate the efficacy of autophagy modulation for the resolution of AD phenotypes in disease-relevant assays and in vitro neuronal models as well as an in vivo model. Our approach is innovative because we have identified mTOR-independent autophagy activators and will identify and validate their unique targets and mechanisms of action in neuronal models to potentially reveal new targets for AD drug discovery. The aims of this proposal will contribute to the achievement of our long-term goal to develop new therapeutics for unmet needs in neurodegenerative diseases. FDA- approved drugs for AD treat the symptoms of the disease but do not improve the underlying cell damage that leads to disease progression, further highlighting the need for novel neuroprotective therapeutic options.