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APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer’s pathology in trisomy 21 neurons

Molecular Psychiatry volume 27, pages 1970–1989 (2022)Cite this article

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Abstract

Trisomy 21 (T21) causes Down syndrome and an early-onset form of Alzheimer’s disease (AD). Here, we used human induced pluripotent stem cells (hiPSCs) along with CRISPR-Cas9 gene editing to investigate the contribution of chromosome 21 candidate genes to AD-relevant neuronal phenotypes. We utilized a direct neuronal differentiation protocol to bypass neurodevelopmental cell fate phenotypes caused by T21 followed by unbiased proteomics and western blotting to define the proteins dysregulated in T21 postmitotic neurons. We show that normalization of copy number of APP and DYRK1A each rescue elevated tau phosphorylation in T21 neurons, while reductions of RCAN1 and SYNJ1 do not. To determine the T21 alterations relevant to early-onset AD, we identified common pathways altered in familial Alzheimer’s disease neurons and determined which of these were rescued by normalization of APP and DYRK1A copy number in T21 neurons. These studies identified disruptions in T21 neurons in both the axonal cytoskeletal network and presynaptic proteins that play critical roles in axonal transport and synaptic vesicle cycling. These alterations in the proteomic profiles have functional consequences: fAD and T21 neurons exhibit dysregulated axonal trafficking and T21 neurons display enhanced synaptic vesicle release. Taken together, our findings provide insights into the initial molecular alterations within neurons that ultimately lead to synaptic loss and axonal degeneration in Down syndrome and early-onset AD.

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Fig. 1: Trisomy 21 neurons express elevated phosphorylated tau and higher Aβ levels.
Fig. 2: Widespread changes in RNA and protein expression in T21 neurons.
Fig. 3: Normalization of copy number of APP or DYRK1A, but not RCAN1 and SYNJ1, rescues elevated phosphorylated tau levels in T21 neurons.
Fig. 4: Global analyses of tau peptides reveal alterations at multiple sites across the tau protein in T21 neurons, a subset of which are rescued by APP and/or DYRK1A copy number normalization.
Fig. 5: Normalization of APP and DYRK1A copy number rescues alterations in cytoskeletal and synaptic vesicle protein networks disrupted in T21 neurons.
Fig. 6: Dysregulation of axonal transport in fAD and T21 neurons.
Fig. 7: Enhanced synaptic vesicle release in T21 neurons mediated by elevated APP and DYRK1A levels.

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Code availability

The MATLAB and ImageJ codes used for this study are available at GitHub: https://github.com/ThomasSchwarzLab/ArrayScanCodes. https://github.com/ThomasSchwarzLab/KymolyzerCodes.

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Acknowledgements

This work also was supported by the Brigham Research Institute, R01AG055909, R01NS117446, U01AG061356, R21AG053827, and R01GM069808. The results published here are in part based on human brain tissue data obtained from the AMP-AD Knowledge Portal (https://adknowledgeportal.synapse.org/). The authors would like to thank Pascal Kaesar for providing guidance and plasmids for the synaptic release assays and to Jeanne Lawrence for generously providing the T21 and T21rev (person #2) iPSC lines.

Author information

Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA, USA

    Chun-I Wu, Elizabeth A. Vinton, Richard V. Pearse II, Aimee J. Aylward, Yi-Chen Hsieh, Yan Bi, Sopefoluwa Adeleye, Seeley Fancher & Tracy L. Young-Pearse

  2. Harvard Medical School, Boston, MA, USA

    Chun-I Wu, Richard V. Pearse II, Keunjung Heo, Yi-Chen Hsieh, Thomas L. Schwarz & Tracy L. Young-Pearse

  3. Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA

    Duc M. Duong & Nicholas T. Seyfried

  4. Department of Neurology, Emory School of Medicine, Atlanta, GA, USA

    Duc M. Duong & Nicholas T. Seyfried

  5. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

    Keunjung Heo & Thomas L. Schwarz

Authors
  1. Chun-I Wu
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  2. Elizabeth A. Vinton
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  3. Richard V. Pearse II
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  4. Keunjung Heo
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  5. Aimee J. Aylward
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  6. Yi-Chen Hsieh
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  7. Yan Bi
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  8. Sopefoluwa Adeleye
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  9. Seeley Fancher
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  10. Duc M. Duong
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  11. Nicholas T. Seyfried
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  12. Thomas L. Schwarz
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  13. Tracy L. Young-Pearse
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Contributions

CW designed experiments, performed experiments, and performed data analysis. EV, AA, YH, YB, SA, and SF performed experiments. RP performed data analysis and revised manuscript drafts. KH performed the trafficking assays and KH and TS designed and analyzed data from these experiments. DD and NS performed and analyzed data from proteomic profiling experiments. TLYP designed the study, performed data analysis, authored manuscript text, revised manuscript drafts, and supervised this work.

Corresponding author

Correspondence to Tracy L. Young-Pearse.

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The authors declare no conflicts of interest.

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Wu, CI., Vinton, E.A., Pearse, R.V. et al. APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer’s pathology in trisomy 21 neurons. Mol Psychiatry 27, 1970–1989 (2022). https://doi.org/10.1038/s41380-022-01454-5

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  • DOI: https://doi.org/10.1038/s41380-022-01454-5

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