Elucidating the Molecular and Cellular Mechanisms Underlying Neurodegeneration Using Advanced Stem Cell-Based Technologies

ongoing

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Despite the significant progress made towards unpacking the pathomechanisms of AD, the molecular and cellular mechanisms underlying AD pathogenesis remain poorly understood. Previous studies mainly relied on animal models that do not capture human-specific biology, monolayer neural cultures that do not capture pathological hallmarks of the disease, and post-mortem tissues that only capture disease end-stage. There is thus a pressing need for new complementary approaches that preserve the disease genetics, mimic disease pathology, and more closely reflect human brain environment. I have developed a chimeric system for transplantation of Induced Pluripotent Stem Cells (iPSC)-derived brain organoids into the mouse brain, providing a powerful platform to study AD under a physiological environment. This project aims to understand the molecular and cellular aberrations underlying AD pathogenesis. I propose to achieve this goal via a novel combination of a chimeric model, iPSC-based patient-specific brain organoids, transcriptomics, epigenetics, and genetic editing approaches. We will determine the disease-associated progressive changes at the transcriptome level, examine the cellular aberrations both in vitro and within the in vivo brain environment, and identify molecular regulators that underlie disease deficits and might enhance susceptibility to AD manifestation. Next, we will define perturbations in the epigenetic landscape associated with AD. Finally, this project seeks to extend towards identifying critical mechanisms that govern the interplay between neurons and the immune system in AD. I anticipate that this research will uncover novel molecular, cellular, and functional mechanisms that govern AD pathology, and may provide a basis for developing future therapeutic strategies.