The application of in vitro‐derived human neurons in neurodegenerative disease modeling

Abstract

The development of safe and effective treatments for age‐associated neurodegenerative disorders is an on‐going challenge faced by the scientific field. Key to the development of such therapies is the appropriate selection of modeling systems in which to investigate disease mechanisms and to test candidate interventions. There are unique challenges in the development of representative laboratory models of neurodegenerative diseases, including the complexity of the human brain, the cumulative and variable contributions of genetic and environmental factors over the course of a lifetime, inability to culture human primary neurons, and critical central nervous system differences between small animal models and humans. While traditional rodent models have advanced our understanding of neurodegenerative disease mechanisms, key divergences such as the species‐specific genetic background can limit the application of animal models in many cases. Here we review in vitro human neuronal systems that employ stem cell and reprogramming technology and their application to a range of neurodegenerative diseases. Specifically, we compare human‐induced pluripotent stem cell‐derived neurons to directly converted, or transdifferentiated, induced neurons, as both model systems can take advantage of patient‐derived human tissue to produce neurons in culture. We present recent technical developments using these two modeling systems, as well as current limitations to these systems, with the aim of advancing investigation of neuropathogenic mechanisms using these models.

Prolonged culturing of iPSC-derived brain endothelial-like cells is associated with quiescence, downregulation of glycolysis, and resistance to disruption by an Alzheimer’s brain milieu

“…We used cells heterozygous for this mutation, APP Swe/+ , along with the isogenic APP wild-type, APP WT . Neurons from these cell lines were differentiated from hiPSCs as previously described in Knupp et al [ 26 ] and D’Souza et al [ 27 ]. hiPSC-neurons from the APP Swe/+ and APP WT lines were cultured in Neural Differentiation media (1:1 DMEM/F12 (Life Technologies, cat no.…”

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

“…Neurodegenerative diseases, particularly those with a protein aggregation component, have been especially hard to model accurately in animals like mice. As such, PSCs have become a very attractive model for this field (for more detailed discussions on the topic see: Riemens et al, 2020 ; Valadez-Barba et al, 2020 ; D'Souza et al, 2021 ). Alzheimer's disease, Parkinson's disease, ALS and Huntington's disease are complex disorders with the vast majority being sporadic, but with familial cases caused by known mutations that provide evidence of strong genetic risk factors, such as ApoE4 (Corder et al, 1993 ).…”

Microphysiological Systems for Neurodegenerative Diseases in Central Nervous System

“…Human iPSC-derived neural cells are favorable for determining these unrevealed risky genes without exogenous gene modification [ 30 ]. Moreover, iPSC-derived neurons show not only genetic phenotypes but also neuropathology, e.g., elevated A levels in patient-derived cells relative to those in healthy cell sources [ 31 , 32 , 33 ].…”