3-D Neural Core/High-Throughput Drug Screening for Alzheimer’s Disease Using 3-D Human Neural Culture Systems

2018 to 2019

Alzheimer’s disease has become a major public health problem—and there is no cure for the disease. Previously, we have developed a novel three-dimensional human neural cell culture model of AD (Alzheimer’s in a Dish), which recapitulates key pathological events in AD in human brain-like environment. In this ongoing project, we have been using our 3D AD cellular model as a platform to screen novel AD drug candidates and identify druggable cellular pathways that can reduce AD pathogenesis. The current research will validate and test the efficacy of lead AD drug candidates in more physiologically relevant 3D cellular models, including 3D cell models from female and male patient-derived AD neurons, and explore their impacts on human AD neurons. The project includes a new pilot drug library screening project from a natural compound library. Overarching goals are to provide novel mechanistic insights how to block the pathological cascade of AD in human neural cells and to find novel AD drug candidates that can be directly applicable in human clinical trials.

2015 to 2017

The “beta-amyloid cascade hypothesis” of Alzheimer’s disease (AD) has provided a major framework for AD drug discovery and has led to many current clinical trials. However, to date, no single in vitro or in vivo AD model has been able to recapitulate the presumed patient pathophysiology: beta-amyloid deposition directly leads to tangles and neurodegeneration. Recently, we created a novel three­ dimensional (3-D) human neural cell culture model of AD using genetically engineered human neural stem cells. Using this unique model, we showed that expression of APP and PSEN1 with familial AD mutations is sufficient to induce extracellular beta-amyloid deposits and robust tauopathy, including hyperphosphorylated tau and detergent-resistant, silver-positive neurofibrillary tangles for the first time (Choi et al., 2014). This human 3-D culture model has great potential to innovate and accelerate the current AD drug screening process. We now propose to use high-throughput drug screening in combination with our 3-D human cellular AD model to identify and characterize novel AD drugs and drug targets that can reduce both beta-amyloid and tau pathologies, which is not feasible using current AD mouse models.

In Aim 1, we will develop a high-throughput screening (HTS) system based on 3-D human cellular AD models (3-D AD-HTS). In Aim 2, we will carry out 3-D AD-HTS using FDA-approved drug libraries and validate the primary hits that reduce beta-amyloid and/or tau pathologies and finally, in Aim 3, we will explore whether the validated candidate drugs rescue the neuronal injuries and functional deficits in the 3-D AD culture model. The overarching goals of this study are to 1) establish a 3-D HTS AD drug screening system based on human 3-D neural cell culture models; 2) find potential AD drug candidates among the FDA-approved drugs (drug repurposing); and 3) identify novel cellular pathways that can regulate both beta-amyloid and tau pathologies. Since no current AD mouse model of beta-amyloid deposition leads to tangles and neurodegeneration, which are both critical aspects of the disease, the human neural cell culture model could serve as a novel, crucial drug discovery platform for AD.