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

调节自噬流作为阿尔茨海默病的治疗策略

• 批准号: 10417514
• 负责人: Swetha Gowrishankar
• 金额: $ 177.38万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417514
• 关键词: APP-PS1; Abeta clearance; Achievement; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-42; Autophagocytosis; Autophagosome; Axon; Behavior; Biogenesis; Biological Assay; Biological Process; Biology; Clinical; Communities; Complex; Defect; Dementia; Development; Disease; Disease Progression; Drug Kinetics; Exhibits; FDA approved; FRAP1 gene; Female; Gliosis; Goals; Homeostasis; Human; In Vitro; Induced pluripotent stem cell derived neurons; Lead; Life; Longevity; Lysosomes; Metabolism; Mission; Modeling; Mus; Nature; Neurodegenerative Disorders; Neurons; Organelles; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Preparation; Prevention; Process; Property; Proteomics; Public Health; Quality of life; Recycling; Research; Resolution; Role; Senile Plaques; Solubility; Structure-Activity Relationship; Symptoms; Testing; Therapeutic; Therapeutic Intervention; United States; Vesicle; age related neurodegeneration; amyloid precursor protein processing; analog; blood-brain barrier penetration; cell injury; design; disease phenotype; drug discovery; drug metabolism; efficacy evaluation; efficacy study; experimental study; improved; in vivo; in vivo Model; innovation; lead optimization; male; mouse model; neuron loss; new therapeutic target; novel; novel therapeutics; prevent; restoration; sex; small molecule; symptom treatment; targeted treatment; therapeutic development; tool

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.

自噬是一种维持细胞稳态的分解代谢细胞回收过程，其失调已导致 与许多疾病有关，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，包括自噬囊泡的积累 和溶酶体中间体以及自噬体内容物的溶酶体加工缺陷。 可以克服这些缺陷的分子自噬激活剂可能会阻止疾病进展 通过恢复细胞稳态和预防神经元细胞损伤。 假设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，可预防疾病进展并改善阿尔茨海默病 该假设将通过该提案的总体目标进行测试，以优化 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模型测定中调节 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不依赖于 mTOR 的自噬。 激活剂，并将在神经模型中识别和验证其独特的目标和作用机制，以 潜在地揭示 AD 药物发现的新目标 该提案的目标将有助于实现这一目标。 我们的长期目标是开发新疗法来满足神经退行性疾病未满足的需求。 FDA- 批准用于治疗 AD 的药物可以治疗该疾病的症状，但不能改善潜在的细胞损伤 导致疾病进展，进一步凸显了对新型神经保护治疗方案的需求。

项目成果

AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network.

AP-4 通过调节跨高尔基体网络关键溶酶体受体蛋白的输出来调节神经元溶酶体的组成、功能和运输。

• 发表时间: 2022-10-01
• 影响因子: 3.3
• 作者: Majumder, Piyali;Edmison, Daisy;Rodger, Catherine;Patel, Sruchi;Reid, Evan;Gowrishankar, Swetha
• 通讯作者: Gowrishankar, Swetha