Laura Moore

Introduction. Alzheimer’s Disease (AD) is the 6^th leading cause of death in the US and it is the only one of the top 10 leading causes that has not been prevented, cured or slowed in recent years ¹. AD is a neurodegenerative disease that slowly causes the patient to exhibit memory loss, cognitive and motor impairment, mood and behavior disorders, as well as sleep disturbances ¹. AD affects the neocortex and hippocampus, specifically targeting pyramidal glutamatergic neurons ². The two hallmarks of AD are extracellular amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyper-phosphorylated Tau, which is a microtubule binding protein ³. The leading theory is that the amyloid plaques lead to the Tau tangles. However, this has yet to be adequately proved through animal studies so progress towards an effective treatment has been lacking. One possible reason for this is that mice do not produce all 6 isoforms of Tau that are found in humans, so mice may not be a good model for human disease ⁴. The answer to our research problem probably lies in 3D in vitro platforms, or even organoids, that can be created more similar to a human neocortex than a mouse or 2D platform.  Methods. Studies were conducted with the use of human iPSC that were induced to become neuroepithelial stem cells ⁵ and progenitor cells (hNPCs)⁶. They then genetically altered them to contain Familial AD (FAD) mutated genes APP and PSEN1 so they would exhibit typical AD symptoms^5,6. These were then grown in 3D platforms constructed from Matrigel⁵ or RADA-16⁶, substances that supply a cytoskeletal framework for the cells to grow on and interact with each other in a natural way. Another model called an organoid is an ectoderm grown for 90 days that represents the natural layers found in a human neocortex⁷. Results. These models have shown significant progress in elucidating the relationship between the Alzheimer’s genes, Aβ amyloid plaques, and Tau tangles. β-amyloid can be observed with a light microscope after 6 weeks, and Tau pathology at 10-14 weeks^5,6.  Conclusion.  With the use of 3D models we should be able to streamline the process of developing new treatments for Alzheimer’s Disease. These models can be used as an adjunct to animal models to move drugs more quickly to human trials.

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6. Kim, Young Hye, Se Hoon Choi, Carla D’Avanzo, Matthias Hebisch, Christopher Sliwinski, Enjana Bylykbashi, Kevin J. Washicosky, et al. “A 3D Human Neural Cell Culture System for Modeling Alzheimer’s Disease.” Nature Protocols 10, no. 7 (July 2015): 985–1006.
7. Raja, Waseem K., Alison E. Mungenast, Yuan-Ta Lin, Tak Ko, Fatema Abdurrob, Jinsoo Seo, and Li-Huei Tsai. “Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes.” PLoS ONE 11, no. 9 (September 13, 2016).