CIRCUITS: Functional Analysis of Alzheimer’s Disease Risk Genes Using Human-Induced Pluripotent Stem Cells

2016 and 2018

2018

Our incomplete understanding of the genetic pathways underlying the development of late-onset Alzheimer’s disease has hampered efforts to treat and cure the disease. Incidences of late-onset Alzheimer’s disease account for the majority of individuals with Alzheimer’s. To address this critical shortcoming, we developed a discovery platform that takes advantage of recent advances in induced pluripotent stem cells (iPSCs), genomics, epigenetics and the technologies of genome editing to identify genes and gene controlling elements driving the development of disease. We have made important technical advances that allow us to identify from different regions of the Alzheimer’s brains the epigenetic landscapes unique to each of the major cell types implicated in the disease. We also have generated several iPSC lines that can be induced to become a specific type of brain cell, and in which a particular gene or its controlling element involved in Alzheimer’s can be turned on or off with high chemical precision. We are leveraging these powerful tools to our discovery platform to identify the critical genetic players and pathways driving Alzheimer’s disease. A better understanding of the genetic dysregulation behind the disease should lead to new and effective therapeutic strategies for the treatment and cure of Alzheimer’s disease.

2016

The vast majority of people with Alzheimer’s disease (AD) suffer from the sporadic, or late-onset form, which causes remain completely unknown. From studies involving thousands of people, researchers have identified a number of genetic variants that may increase one’s risk for sporadic AD. However, little is understood regarding why these small changes impact one’s risk to develop AD. In this work, we will use the cutting-edge genome editing technique CRISPR/Cas9 to introduce AD-associated genetic variants identified through genome-wide analysis into reprogrammed human stem cells. We will differentiate human stem cells harboring these variants into various cell types populating the brain—including neurons, astrocytes and microglia—and study the effects of these variants in these different cell types. The proposed study will provide mechanistic insights into why some genetic variants found in the population may predispose some individuals to an increased risk for AD.


Funding to Date

$860,000

Focus

Foundational Genetics, Whole Genome Sequencing and Epigenetics

Researchers

Li-Huei Tsai, Ph.D.


Manolis Kellis, Ph.D.