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

Ye Jin Park; Tzu Chiao Lu; Tyler Jackson; Lindsey D. Goodman; Lindsey Ran; Jiaye Chen; Chung Yi Liang; Erin Harrison; Christina Ko; Xi Chen; Baiping Wang; Ao Lin Hsu; Elizabeth Ochoa; Kevin F. Bieniek; Shinya Yamamoto; Yi Zhu; Hui Zheng; Yanyan Qi; Hugo J. Bellen; Hongjie Li

doi:10.1016/j.neuron.2025.04.017

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

Ye Jin Park, Tzu Chiao Lu, Tyler Jackson, Lindsey D. Goodman, Lindsey Ran, Jiaye Chen, Chung Yi Liang, Erin Harrison, Christina Ko, Xi Chen, Baiping Wang, Ao Lin Hsu, Elizabeth Ochoa, Kevin F. Bieniek, Shinya Yamamoto, Yi Zhu, Hui Zheng, Yanyan Qi, Hugo J. Bellen, Hongjie Li

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2065-2082.e8
Journal	Neuron
Volume	113
Issue number	13
DOIs	https://doi.org/10.1016/j.neuron.2025.04.017
State	Published - Jul 9 2025

Keywords

Alzheimer's disease
Drosophila
LDH-high cluster
aging
brain-body communication
cell atlas
neurodegeneration
single-nucleus RNA-seq

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2025.04.017

Cite this

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. https://doi.org/10.1016/j.neuron.2025.04.017

Park, YJ, Lu, TC, Jackson, T, Goodman, LD, Ran, L, Chen, J, Liang, CY, Harrison, E, Ko, C, Chen, X, Wang, B, Hsu, AL, Ochoa, E, Bieniek, KF, Yamamoto, S, Zhu, Y, Zheng, H, Qi, Y, Bellen, HJ & Li, H 2025, 'Distinct systemic impacts of Aβ42 and Tau revealed by whole-organism snRNA-seq', Neuron, vol. 113, no. 13, pp. 2065-2082.e8. https://doi.org/10.1016/j.neuron.2025.04.017

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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.",

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AU - Lu, Tzu Chiao

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AU - Chen, Jiaye

AU - Liang, Chung Yi

AU - Harrison, Erin

AU - Ko, Christina

AU - Chen, Xi

AU - Wang, Baiping

AU - Hsu, Ao Lin

AU - Ochoa, Elizabeth

AU - Bieniek, Kevin F.

AU - Yamamoto, Shinya

AU - Zhu, Yi

AU - Zheng, Hui

AU - Qi, Yanyan

AU - Bellen, Hugo J.

AU - Li, Hongjie

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N2 - 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.

AB - 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.

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KW - single-nucleus RNA-seq

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

Abstract

Keywords

ASJC Scopus subject areas

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