Studying Lysosomal Vulnerability in Aging and Alzheimer's Disease

The objective is to achieve an integrated understanding of how lysosomal defects correlate with an increase of age and are exacerbated in Alzheimer’s disease, leading to neurodegeneration.

Lysosomal vulnerability is critical to the development of Alzheimer’s disease (AD), whereas the molecular basis of the deficit in human neurons is not fully understood. I harness the lineage reprogramming technology to transdifferentiate human somatic cells into neurons (tNeurons) to facilitate the learning of disease biology and test therapeutic strategies for AD. The outcomes will advance our understanding of lysosomal dysfunction and lysosome-targeting compounds for AD and potentially other dementias.

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.