Studying Lysosomal Vulnerability in Aging and Alzheimer's Disease
In Aim 1, we will develop a cell model for aging and Alzheimer's disease (AD) based on the transdifferentiation of human adult fibroblasts into cortical neurons. The transdifferentiated neurons (tNeurons) will be used for proteome-wide and mechanistic studies of lysosomal vulnerability. In Aim 2, we will develop a human neuron platform using tNeurons for screening compounds that can slow or reverse AD phenotypes. The compound candidates will be tested for their ability to promote protein aggregate clearance and neuronal health in the cell and mouse models for AD.
The direct conversion of human somatic cells into neurons overcomes rejuvenation. This allows for aging signature preservation and detailed biological characterization, which can provide a better understanding of the aging trajectory of human neurons and prediction of risk for developing AD. The biggest challenge for AD treatment is a lack of understanding the biological target of drugs. Using the tNeuron platform for unbiased phenotypic and genome-wide screening is a novel approach to investigate compound mechanism-of-action and identify new compounds that promote neuronal survival in AD. The completion of this proposal is anticipated to highlight that human tNeurons provide a tractable system equipped with a capacity to capture signals of neuronal aging and AD. The outcomes will provide novel insights into the role of lysosomes in the aging and neurodegenerative process in AD, and its therapeutic implications for AD. Ultimately, we hope that the accumulating research work will eventually be used to quantitatively predict individual neuronal healthspan, discover biomarkers, stratify disease risk, and develop personalized interventions for AD and related dementias.