APA
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Cai, Y., Kanyo, J., Wilson, R., Bathla, S., Cardozo, P. L., Tong, L., … Grutzendler, J. (2025). Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease. Nature Aging.
Chicago/Turabian
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Cai, Yifei, Jean Kanyo, Rashaun Wilson, S. Bathla, P. L. Cardozo, Lei Tong, Shanshan Qin, et al. “Subcellular Proteomics and IPSC Modeling Uncover Reversible Mechanisms of Axonal Pathology in Alzheimer’s Disease.” Nature Aging (2025).
MLA
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Cai, Yifei, et al. “Subcellular Proteomics and IPSC Modeling Uncover Reversible Mechanisms of Axonal Pathology in Alzheimer’s Disease.” Nature Aging, 2025.
BibTeX Click to copy
@article{yifei2025a,
title = {Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease},
year = {2025},
journal = {Nature Aging},
author = {Cai, Yifei and Kanyo, Jean and Wilson, Rashaun and Bathla, S. and Cardozo, P. L. and Tong, Lei and Qin, Shanshan and Fuentes, Lukas A. and Pinheiro-de-Sousa, Iguaracy and Huynh, Tram and Sun, Liyuan and Mansuri, M. and Tian, Zichen and Gan, Hao-Ran and Braker, Amber and Trinh, Hoang Kim and Huttner, A. and Lam, Tukiet and Petsalaki, E. and Brennand, Kristen J. and Nairn, AC and Grutzendler, J.}
}
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer’s disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated in spheroids. Furthermore, phosphorylated mTOR levels in spheroids correlated with AD severity in humans. Notably, mTOR inhibition in iPSC-derived neurons and mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and therapeutic targets for axonal pathology in neurodegeneration.