Distinct systemic impacts of Aβ42 and Tau revealed by whole-organism snRNA-seq.

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.