ALZHEIMERS RESEARCH PROJECT: Investigating Early and Cell-Autonomous Mechanisms of Neurodegeneration Using Human Brain Organoids

National Institute On Aging

Investigators

Abstract

This project studies neurodegeneration using 3D multicellular brain organoids to investigate how loss-of-function GRN mutations influence disease progression. Initially, we are generating cortical organoids carrying GRN mutations and comparing them to isogenic controls to identify molecular and cellular signatures of early disease processes. To better replicate the in vivo brain environment, these organoids are co-transplanted with iPS-derived glial cells, including iAstrocytes and iMicroglia. This latest model will allow us to study glial cells contribution to neurodegeneration. In subsequent phases, we plan to generate thalamic and ganglionic eminence organoids and transplant them with additional iPS-derived non-neuronal cell types, such as endothelial cells and fibroblasts, to further increase physiological relevance. Throughout the course of the project, proteomic, single-cell and spatial transcriptomic analyses will be performed at multiple time points. Long-read sequencing will provide insights into methylation patterns and splicing impairments. Electrophysiological assessments using multi-electrode arrays, patch-clamp and calcium imaging will be conducted in parallel to evaluate functional outcomes. Complementing these approaches, a collaborative inter-laboratory project employs multidimensional MRI to non-invasively monitor structural and cellular changes in organoids over time. Together, these integrated analyses will enhance our understanding of GRN-driven neurodegeneration and support the development of future therapeutic strategies by uncovering critical disease mechanisms and cellular targets.