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

自噬是维持细胞内稳态的分解代谢细胞再循环过程，其失调 与许多疾病有关，包括神经退行性疾病如阿尔茨海默病（AD）。 AD是一种与年龄相关的神经退行性疾病，在美国影响超过500万人。 在AD中观察到自噬和溶酶体缺陷，包括自噬囊泡的积聚 和溶酶体中间体以及自噬体内容物的有缺陷的溶酶体加工。小- 分子自噬激活剂可以克服这些缺陷，可能会阻止疾病的进展 通过恢复细胞内稳态和预防神经元细胞损伤。我们的中央 假设是小分子自噬激活剂将恢复自噬和溶酶体稳态， 表现出神经保护作用，将防止疾病进展和改善阿尔茨海默病 体内症状将通过本提案的总体目标来检验这一假设， 自噬激活剂作为体内工具化合物和药物先导物，并评估自噬的功效 在疾病相关测定和体外神经元模型中调节AD表型的分辨率 作为体内模型。我们的方法是创新的，因为我们已经确定了mTOR非依赖性自噬 激活剂，并将确定和验证其独特的目标和作用机制，在神经元模型， 可能揭示AD药物发现的新靶点。本提案的目的将有助于实现 我们的长期目标是为神经退行性疾病的未满足需求开发新的治疗方法。FDA- 批准的AD药物治疗疾病的症状，但不能改善潜在的细胞损伤， 导致疾病进展，进一步强调了对新的神经保护治疗选择的需要。

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.