Modeling Alzheimer’s Disease in Specific Subtypes of Human Neurons Through Direct Neuronal Reprogramming of Patient Fibroblasts

2016-2019

2019

The risk of developing Alzheimer’s disease increases with age, and identifying the cellular processes that occur during brain aging will provide fundamental insights into the pathogenesis of AD. The ability to derive and grow human neurons that mimic neurons of elderly individuals will offer experimental tools to investigate cellular properties in aged human neurons and their relation to the increased risk for Alzheimer’s disease. We previously have demonstrated the feasibility of generating human neurons by expressing small RNA molecules termed microRNAs in an abnormal place—in this case, dermal fibroblasts. This change in the location alters the “fate” of cells as they are converted directly to neurons. The overall goal of the Cure Alzheimer’s Fund grant was to examine age-associated cellular properties in human neurons generated by the microRNA-mediated direct conversion of adult fibroblasts to neurons, and further develop cellular reprogramming approaches for producing the type of human neurons affected in AD. From this project, we learned that human neurons generated through direct neuronal conversion retained the age information stored in the starting fibroblasts, resulting in the generation of human neurons that reflect the age of fibroblast donors. This maintenance of age in converted neurons was found to be an integral component of recapitulating cellular phenotypes associated with adult-onset neurodegenerative disorders. Also, the Cure Alzheimer’s Fund grant offered opportunities to refine the cellular reprogramming approaches to generate different types of human neurons affected in AD. Our current research goal is to use defined subtype-specific reprogramming approaches to model AD from the patient samples and investigate the pathogenesis of AD.

2016-2018

The ability to derive and grow human neurons in tissue culture from elderly individuals will offer invaluable tools to study how advancing aging, the strongest risk factor for Alzheimer’s disease, affects neuronal properties later in life. My research team developed an experimental approach to convert (reprogram) skin fibroblast cells from human individuals directly into neurons without the usual requirement of reverting the cells back to stem cell stages. Our method utilizes small molecules called microRNAs, which can be combined with additional genetic factors to generate specific types of neurons. Here, we propose to devise a microRNA-based reprogramming technique to generate neuronal subtypes affected in early stages of Alzheimer’s disease with high efficiency and specificity. Using this approach, we will generate human neurons from the donors of multiple age groups, and analyze age-related signatures in converted neurons across the age spectrum. If this project succeeds, we will be able to generate human neurons reflecting all ages, and discover the biological changes that occur at different stages of life. With these powerful tools in hand, we will be able to elucidate how neurons age and function differently across the age spectrum. Our work eventually will offer insights into cellular properties intrinsic in aging neurons that make them susceptible to neurodegenerative diseases later in life. By devising biomarkers that indicate the aging status of neurons, our work ultimately will lead to an experimental platform to screen for drugs that one day may promote healthy brain function throughout life.


Funding to Date

$645,000

Focus

Foundational Genetics, Individual Projects (Other), Other Areas of Investigation, Translational Research

Researchers

Andrew S. Yoo, Ph.D.