Park, Y.J., Lu, T.C., Jackson, T., Goodman, L.D., Ran, L., Chen, J., Liang, C.Y., Harrison, E., Ko, C., Chen, X., Wang, B., Hsu, A.L., Ochoa, E., Bieniek, K.F., Yamamoto, S., Zhu, Y., Zheng, H., Qi, Y., Bellen, H.J., Li, H. (2025). Distinct systemic impacts of Aβ42 and Tau revealed by whole-organism snRNA-seq.  Neuron 113(13): 2065--2082.e8.

FBrf0262893

Research paper

Both neuronal and peripheral tissues become disrupted in Alzheimer's disease (AD). However, a comprehensive understanding of how AD impacts different tissues across the whole organism is lacking. Using Drosophila, we generated an AD Fly Cell Atlas (AD-FCA) based on whole-organism single-nucleus transcriptomes of 219 cell types from flies expressing AD-associated proteins, either human amyloid-β 42 peptide (Aβ42) or Tau, in neurons. We found that Aβ42 primarily affects the nervous system, including sensory neurons, while Tau induces accelerated aging in peripheral tissues. We identified a neuronal cluster enriched in Aβ42 flies, which has high lactate dehydrogenase (LDH) expression. This LDH-high cluster is conserved in 5XFAD mouse and human AD datasets. We found a conserved defect in fat metabolism from both fly and mouse tauopathy models. The AD-FCA offers new insights into how Aβ42 or Tau systemically and differentially affects a whole organism and provides a valuable resource for understanding brain-body communication in neurodegeneration.

PMC12245608 (PMC) (EuropePMC)