Human Pluripotent and Multipotent Stem Cells as Tools for Modeling Neurodegeneration

摘要

Sophisticated protocols for the derivation of defined somatic cell cultures from human pluripotent stem cells have opened fascinating prospects for modeling human diseases in vitro. This is particularly relevant for the study of nervous system disorders, where so far the lack of primary tissue has precluded the development of standardized, cell-based in vitro models. We have recently described the derivation of long-term, self-renewing neuroepithelial stem cells (lt-NES cells) from human pluripotent stem cells. Here we report on how this stable somatic stem cell population can be used to study pathogenic mechanisms underlying Alzheimer's disease (AD) and polyglutamine disorders. Specifically, we demonstrate that human neurons derived from lt-NES cells exhibit the entire machinery required for proteolytic processing of the amyloid precursor protein (APP) and are suitable for studying mutants associated with familial variants of AD as well as pharmaceutical compounds modulating the formation of amyloid beta (Abeta). Using induced pluripotent stem cell-derived lt-NES cells from patients with Machado-Joseph disease as an example, we further show that this cellular model provides experimental access to the molecular events initiating pathological protein aggregation - one of the most common denominators of human neurodegenerative disease.