ADPD Mechanisms and Therapeutics - Research Program

Project: Systematic Alzheimer's Disease Drug ReposiTioning (SMART) framework Based on Bioinformatics-guided Phenotype Screening and Imagomics Modeling

The SMART framework for drug repositioning and discovery.

Combining the systems pharmacology and drug repositioning expertise of the Wong Lab at the Houston Methodist with the Alzheimer’s biology expertise of the Kim and Tanzi labs at Massachusetts General Hospital, we propose a SysteMatic Alzheimer’s disease drug ReposiTioning (SMART) framework based on bioinformatics-guided phenotype screening. Reformatting a novel three-dimensional human neural stem cell culture model of AD (a.k.a. Alzheimer's in a dish) developed in the Kim and Tanzi labs for high content screening, the Wong lab screened 2,640 known drugs and bioactive compounds and obtained a panel of 38 primary hits that strongly inhibit β-amyloid-driven p-tau accumulation. We hypothesize that iteratively running relatively small screens with our novel 3D cell model and applying artificial intelligence (AI) modeling to the transcriptomic profiles of the screening hits will allow us to quickly obtain a panel of robust novel drug candidates for AD and gain an in-depth understanding of disease mechanisms from those repositioned drug candidates, which will subsequently improve the success rate of predicting novel hits. Success of this work will lead to new AD therapeutic compounds ready for translation into clinical trials and a deeper understanding of molecular mechanisms of AD pathophysiology. In addition, the SMART framework can be generalizable to other big data driven drug discovery studies.

Project: Brain Microenvironment Crosstalk Modeling and Combination Drug Repositioning

Identification of novel AD-specific crosstalk pathways among neurons and glial cells using the SCRBI explorer and 3D human cell culture models of AD.

There is mounting evidence that non-neuronal brain cells including astrocytes, oligodendrocytes, and microglia, play crucial roles in Alzheimer's disease pathogenesis by interacting with neurons in various stages of the disease. Understanding altered neuron-glia and glia-glia crosstalk in AD is essential to comprehensively understand pathogenic cascade of AD, which may hold the key for identifying therapeutic targets. Recent progresses in "single-cell biology" makes it possible explore pathological pathways of AD at the cellular level. These unbiased, cell-type specific datasets provide a new insight how different brain cells and their interactions contribute to AD pathology.

This project aims to develop a crosstalk modeling tool and human cellular models to identify altered neuron-glia and glia-glia crosstalk pathways in AD. We believe that the combination of multi-cellular systems biology modeling and novel AD models will identify AD-specific neuron-glia and glia-glia crosstalk pathways and novel drug targets. We are developing a multicellular systems biology modeling tool, Single-Cell Resolution Brain Interactome (SCRBI) Explorer to investigate intercellular crosstalk networks among different subgroups of neurons and glial cells and analyze cell-type and subgroup omics data to predict crosstalk pathways in a wholistic and unbiased fashion. Identified pathways and ligand and receptor pairs will be evaluated for their therapeutic potentials. The success of this study will provide a powerful multi-cellular systems biology tool to unbiasedly model and identify neuron-glia and glia-glia crosstalk pathways and novel targets for AD therapeutics.

Project: Identification of Mechanisms and Potential Therapeutic Substrates for AD via Systems Neurobiology Approaches

Development of new cellular models of AD/PD and conducting high throughput screening FDA-approved drugs on imaging-based cell assays and preclinical studies to evaluate the translational potential of newly-identified repositioned drug candidates. Neuroscience and bioinformatics tools are deployed and integrated to study AD&PD at molecular, cellular, organ, and whole system levels on multiple platforms (in silico, in vitro, and in vivo). Drug efficacy, PK/PD, and chronic toxicity are examined in several transgenic mouse models.

This project aims to identify novel mechanisms underlying the complex etiology of AD and potential therapeutic substrates, focusing on key substrates contributing the neurodegeneration or mediating the complex interaction between AD pathological events. Understanding the molecular and cellular mechanisms for the neurodegeneration at early disease stages of Alzheimer's disease will help identify potential effective therapeutic targets for this devastating disease. Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in AD, while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD. We have developed a workflow by integrating computational and experimental neurobiology methods to identify novel factors involved in the early neurodegeneration and brain vulnerability in AD. We examine neurodegeneration-specific gene signatures from sporadic AD patients and synaptic protein changes in transgenic AD mice. Subsequentially, we will assess the association of a top candidate gene with AD and investigate its mechanistic role in neurodegeneration.

Project: In vitro Drug Screening and in vivo Validation of Repositioned Drugs and Traditional Chinese Medicine Compounds for AD/PD Therapeutics

In this project, we are screening known drugs or bioactive compounds as well as herbal compounds of traditional chinese medicine (TCM) on human-derived cellular models of AD/PD and identifying drug hits via systems biology methods for evaluation on transgenic animal models. Disturbed proteostasis is known as a key event contributing to cell death in a variety of neurodegenerative diseases. Abeta/tau aggregates in AD and alpha-synuclein accumulation in PD can be reproduced in human cells (i.e. iPSC-derived neurons) while promoting the clearance of aggregated tau or alpha-synuclein has the potential to translate into therapeutics. Since the development of new therapies is a risky, costly and prolonged process, repurposing known drugs or bioactive compounds is considered an attractive strategy for drug development. Promising repositioning drug hits will be tested on mice bearing disease-relevant mutant before clinical trials. We perform automated drug screening using FDA-approved drug libraries and TCM herbal compounds to identify drug hits reducing toxically modified tau proteins or wild type of alpha-synuclein. We standardized a pipeline for preclinical drug testing in small animals and set up an animal behavioral suite for phenotype examination via Morris water maze, fear conditioning system, locomotion system, and Rotarod.