The looming specter of 13.8 million Americans with Alzheimer's disease (AD) by the year 2050 motivates us to expand our biomedical research paradigm outside of the typical """"""""cell line to rodent to human trials"""""""" model. The disappointing performance of all AD drugs that have come to Phase III clinical trials to date also forces us to think more creatively about how to study the mechanisms that underlie neurodegeneration. The advent of human induced pluripotent stem cells (iPSCs) allows us to create disease models from patients with sporadic AD as well as from those with defined familial mutations. In addition, we can use cutting-edge genome editing techniques, such as the Crispr/Cas system, to introduce disease-associated mutations into the genome of otherwise healthy human derived pluripotent cells. In the past five years, neuroscientists have made incredible advances in the creation of different brain cell types, such as neurons, astrocytes, and oligodendrocytes, from human-derived pluripotent cells. What is lacking, however, is a human cellular model of neuroinflammation, a critical component of all neurodegenerative disorders, including AD. In the current application, we describe the creation of human microglia, the brain's """"""""immune"""""""" cell, from patient-derived and control pluripotent cells. We propose a comprehensive set of experiments that will determine the role that known and novel AD-associated genes play in these cells using cutting-edge genome editing techniques combined with high-throughput functional assays, transcriptomic profiling, and high-resolution proteomics.

Public Health Relevance

Recent genome-wide association (GWAS) and gene expression studies in human Alzheimer's disease (AD) have revealed a striking preponderance of microglial and immune-associated genes. In the current proposal, we describe the creation of a novel human cellular model that will examine the role of AD-associated genes in microglia derived from control and patient-derived induced human pluripotent stem cells (iPSCs). In addition, we will use genome-editing techniques to create isogenic human pluripotent stem cell lines with defined mutations in AD risk genes, and will differentiate these into multiple neural cel types that include microglia and various neuronal subtypes that will be used for functional and genomic studies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M1))
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
Internal Medicine/Medicine
Schools of Arts and Sciences
United States
Zip Code
Lin, Yuan-Ta; Seo, Jinsoo; Gao, Fan et al. (2018) APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron 98:1294
Ma, Haiting; Wert, Katherine J; Shvartsman, Dmitry et al. (2018) Establishment of human pluripotent stem cell-derived pancreatic ?-like cells in the mouse pancreas. Proc Natl Acad Sci U S A 115:3924-3929
Lin, Yuan-Ta; Seo, Jinsoo; Gao, Fan et al. (2018) APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron 98:1141-1154.e7
Mungenast, Alison E; Siegert, Sandra; Tsai, Li-Huei (2016) Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells. Mol Cell Neurosci 73:13-31
Raja, Waseem K; Mungenast, Alison E; Lin, Yuan-Ta et al. (2016) Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One 11:e0161969
Muffat, Julien; Li, Yun; Yuan, Bingbing et al. (2016) Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med 22:1358-1367