As a postdoctoral researcher, I am currently focused on uncovering the subcellular proteomes of neurons and glial cells and characterizing the molecular and cellular functions of these compartments in Alzheimer’s disease. To achieve this, I have developed a multidisciplinary toolset comprising molecular and cellular biology, imaging, and bioinformatics approaches, including proximity labeling proteomics, iPSC-induced human neurons and glia for disease modeling, high-resolution confocal imaging, longitudinal in vivo two-photon imaging, super-resolution pan-expansion microscopy, electron microscopy, spatial transcriptomics, RNA in situ hybridization, and bioinformatics analysis. I have applied these tools to investigate Alzheimer’s disease models, including human AD postmortem brains, human iPSC-derived neuron-glia co-culture AD model, and AD-model mice.

My recent work has focused on understanding the formation of plaque-associated axonal spheroids (PAAS) in Alzheimer’s disease. PAAS disrupt axonal electrical conduction and neuronal network function and correlate with AD severity, but their formation mechanisms are not well understood. I have used proximity labeling proteomics of axonal spheroids in human AD postmortem brains and mice to uncover the molecular architecture of PAAS. I also developed a human iPSC-derived AD model that recapitulates PAAS pathology for mechanistic studies. Through these approaches, I identified hundreds of previously unknown PAAS-enriched proteins and signaling pathways, including PI3K/AKT/mTOR. I found that phosphorylated mTOR was highly enriched in PAAS and strongly correlated with disease severity in humans. Importantly, pharmacological mTOR inhibition in iPSC-derived human neurons or AAV-mediated knockdown in mice led to a marked reduction of PAAS pathology. These findings provide a novel platform to examine mechanisms of axonal pathology in neurodegeneration and to evaluate the therapeutic potential of novel targets. I am currently preparing a co-corresponding first-author article for publication in a peer-reviewed journal (in revision, also available on bioRxiv).

Additionally, I have contributed to a related project that demonstrated the functional impact of axonal spheroids in disrupting axonal electrical conduction and impairing neuronal circuitries. In this project, I elucidated the super-resolution subcellular structures within axonal spheroids, which allowed me to co-author a research article in Nature (2022).