3D Brain Tissue System for Modeling Resilience to Alzheimer's Disease and Drug Discovery

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PROJECT SUMMARY/ABSTRACT An alternative approach to discovering the causes of Alzheimer’s disease (AD) for the purposes of prevention, diagnosis, and treatment is to research individuals who remain cognitively healthy despite significant genetic risk or pathological burden, a phenomenon termed cognitive resilience. Our quest to understand the nature of cognitive resilience to normal aging and AD in the first genetically diverse AD mouse population (the AD-BXDs) that models the genetic, transcriptomic, and phenotypic heterogeneity of human late-onset AD yielded novel targets for resilience-based therapeutics. To rapidly identify compounds that will likely promote cognitive resilience in preclinical studies (in vivo) and beyond, there is a critical need for a system that recapitulates the key features of the AD brain including morphology, cell-cell interactions, and neural network functions in a dish (in vitro). We propose to develop a 3D co-culture system with neurons, astrocytes, and microglia that exploits established differences in the onset and progression of cognitive symptoms in the AD-BXDs to investigate cellular resilience to AD and validate this system for future discovery of novel resilience-based therapeutics. Notably, the translational relevance of compounds will be critically evaluated in vivo and by cross-species analyses that we and others developed using a variety of genetic, omics and clinical data. Our long-term goal is to develop personalized in vitro 3D assays to study, quantitatively and mechanistically, how aging changes cellular resiliency across a broad range of neuropathologies to develop novel, targeted interventions to enhance cognitive health across a broad spectrum of neurodegenerative diseases for diverse populations, leveraging our partnerships with pharmaceutical companies such as Icagen.