TOWARD 3D HUMAN BRAIN-LIKE TISSUES FOR TARGETING DYSREGULATED SYNAPSE AND PROTEOSTASIS MECHANISMS IN ALZHEIMER'S DISEASE

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ABSTRACT. Alzheimer’s disease (AD) is a neurodegenerative disorder affecting 5.8 million people in the US alone with an estimated $290 billion in annual costs. The disease is characterized by significant memory loss and behavioral abnormalities that are often devastating to quality of life. Memory and behavior are directly related to the underlying changes of the central nervous system (CNS) brain tissue. While many types of CNS abnormalities are differentially reported in AD studies, dysregulated synapse maintenance is consistently found to be altered across AD model systems. Mechanistically, synapse alterations have been shown to converge on many pathways related to proteostasis – including mTOR, macroautophagy, and ubiquitin-proteasome system (UPS) pathways – suggesting a potential unifying approach for treating AD. To date, no effective therapy targeting these pathways exists, owing in part to our nascent understanding of the interplay between these processes in the AD brain. Thus, there is a need to deepen our understanding of these mechanisms as well as to develop novel approaches to target them. Traditionally, mechanistic knowledge of AD has been gained with in vivo animal models and with analyses of post-mortem human brains. However, current animal models of AD are not fully representative of the human condition, and analyses in human brains suffer from a lack of supply, throughput, and experimental control. Induced pluripotent stem cells (iPSCs) have enabled access to live human neurons, but associated studies have largely been performed on 2D plastic surfaces. We propose a 3D material- based approach to enable the study of dysregulated synapse maintenance and proteostasis mechanisms of AD in humans. Compared to alternative 3D models, such as organoids, our tissue engineering approach provides for a highly reproducible, custom design of biophysical and biochemical cell-ECM interactions. Our proposed entry point into these questions is with iPSCs derived from patients with mutant presenilin-1 (PSEN1), one of the most well characterized familial mutations causative of AD. Our 3D models will incorporate human ADPSEN1 iPSC-derived neurons (iNeurons) to mimic key cell-cell interactions known to be important in synapse maintenance. Upon successful completion of the proposed aims, we will have developed 3D human brain-like tissues allowing for more in depth analysis of mechanisms linking dysregulated synapses and network activity with proteostasis pathways. These models can be utilized as additional tools in the drug discovery and validation pipeline, offering unique relevance compared to other in vitro human and in vivo mouse model systems.