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.
Modeling Neuronal Aging in Specific Subtypes of Human Neurons by MicroRNA-Mediated Neuronal Reprogramming
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