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

Neuron. 2025 Jul 9;113(13):2065-2082.e8. doi: 10.1016/j.neuron.2025.04.017. Epub 2025 May 16.

Abstract

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.

Keywords: Alzheimer’s disease; Drosophila; LDH-high cluster; aging; brain-body communication; cell atlas; neurodegeneration; single-nucleus RNA-seq.

MeSH terms

  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides* / genetics
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Disease Models, Animal
  • Drosophila
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Peptide Fragments* / genetics
  • Peptide Fragments* / metabolism
  • Tauopathies / genetics
  • Tauopathies / metabolism
  • Transcriptome
  • tau Proteins* / genetics
  • tau Proteins* / metabolism

Substances

  • Amyloid beta-Peptides
  • tau Proteins
  • amyloid beta-protein (1-42)
  • Peptide Fragments