Abstract
Several iPSC-derived three-dimensional (3D) cultures have been generated to model Alzheimer’s disease (AD). While some AD-related phenotypes have been identified across these cultures, none of them could recapitulate multiple AD-related hallmarks in one model. To date, the transcriptomic features of these 3D models have not been compared with those of human AD brains. However, these data are crucial to understanding the pertinency of these models for studying AD-related pathomechanisms over time. We developed a 3D bioengineered model of iPSC-derived neural tissue that combines a porous scaffold composed of silk fibroin protein with an intercalated collagen hydrogel to support the growth of neurons and glial cells into complex and functional networks for an extended time, a fundamental requisite for aging studies. Cultures were generated from iPSC lines obtained from two subjects carrying the familial AD (FAD) APP London mutation, two well-studied control lines, and an isogenic control. Cultures were analyzed at 2 and 4.5 months. At both time points, an elevated Aβ42/40 ratio was detected in conditioned media from FAD cultures. However, extracellular Aβ42 deposition and enhanced neuronal excitability were observed in FAD culture only at 4.5 months, suggesting that extracellular Aβ deposition may trigger enhanced network activity. Remarkably, neuronal hyperexcitability has been described in AD patients early in the disease. Transcriptomic analysis revealed the deregulation of multiple gene sets in FAD samples. Such alterations were strikingly similar to those observed in human AD brains. These data provide evidence that our patient-derived FAD model develops time-dependent AD-related phenotypes and establishes a temporal relation among them. Furthermore, FAD iPSC-derived cultures recapitulate transcriptomic features of AD patients. Thus, our bioengineered neural tissue represents a unique tool to model AD in vitro over time.
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Data availability
Datasets generated and analyzed in this study can be found in the published article and its supplementary information files. Supplementary information is available at MP’s website. Additional information are available from the corresponding author. ROSMAP resources can be requested at https://www.radc.rush.edu. The NanoString data has been stored on Synapse and is available at https://doi.org/10.7303/syn51471664.
Material availability
A materials transfer agreement covers the TG3 antibody provided by the Feinstein Institutes for Medical Research and the Albert Einstein College of Medicine.
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Acknowledgements
We thank Dr. D. Selkoe (Brigham and Women’s Hospital, Boston) for kindly providing us with the R1282 antibody. We also thank Rachel Willen, Edward K. Robinson, Griffin Sigal, and Isabel Paine for their technical support.
Funding
This work was supported by awards from the National Institutes of Health: 1R21AG065792 (to GT), 5R01AG061838 (to GT, PGH, and DLK), R01AG055909 (to TLYP), and U54AG054345 (to GWC). ROSMAP is supported by P30AG10161, P30AG72975, R01AG15819, R01AG17917. U01AG46152, U01AG61356 (to DAB).
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The authors confirm contributions to the manuscript as follows: conceptualization: SL, GT; data curation: SL, RSP, NR; formal analysis: SL, RSP, NR; investigation: SL, NR, BM, WK, WLC; methodology: SL, RSP, NR, GWC; resources: WLC, GWC, DAB, TLYP, DLK; project administration: GT; supervision: SL, GWC, DLK, GT; validation: SL, RSP, NR, BM, WK, GT; visualization: SL, RSP, NR; writing - original draft preparation: SL, RSP, NR, GT; writing - review and editing: SL, RSP, NR, BM, WK, WLC, PGH, DAB, TLYP, GWC, DLK, GT.
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Lomoio, S., Pandey, R.S., Rouleau, N. et al. 3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer’s disease. Mol Psychiatry 28, 5390–5401 (2023). https://doi.org/10.1038/s41380-023-02147-3
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DOI: https://doi.org/10.1038/s41380-023-02147-3
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