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.