Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation Journal Article
| Authors: | Sonustun, B.; Vahsen, B. F.; Ledesma-Terrón, M.; Li, Z.; Tuffery, L.; Xu, N.; Calder, E. L.; Jungverdorben, J.; Weber, L.; Zhong, A.; Miguez, D. G.; Monetti, M.; Zhou, T.; Giacomelli, E.; Studer, L. |
| Article Title: | Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation |
| Abstract: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron (MN) loss. The most common genetic cause, a hexanucleotide repeat expansion in C9orf72 (C9-ALS), disrupts microglial function, contributing to neuroinflammation, a key disease driver. To investigate this, we developed a three-dimensional spinal microtissue (SM) model incorporating human induced pluripotent stem cell (hiPSC)-derived MNs, astrocytes, and microglia. Screening 190 Food and Drug Administration (FDA)-approved compounds, we identified sartans—angiotensin II receptor I blockers (ARBs)—as potent inhibitors of neuroinflammation. Telmisartan, a highly brain-penetrant ARB, significantly reduced the levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and rescued MN loss in C9-ALS SMs. Our findings suggest that C9-ALS microglia drive MN toxicity and that telmisartan can effectively mitigate inflammation and preserve MN viability. This work lays the groundwork for modeling disease-related neuroinflammation and points to telmisartan as a therapeutic candidate worth further exploration for treating C9-ALS. © 2025 The Authors |
| Keywords: | motor neurons; astrocytes; microglia; amyotrophic lateral sclerosis; neuroinflammation; drug screen; 3d microtissue; c9orf72; sartans; triculture |
| Journal Title: | Stem Cell Reports |
| Volume: | 20 |
| Issue: | 7 |
| ISSN: | 2213-6711 |
| Publisher: | Cell Press |
| Date Published: | 2025-07-08 |
| Start Page: | 102535 |
| Language: | English |
| DOI: | 10.1016/j.stemcr.2025.102535 |
| PROVIDER: | scopus |
| PUBMED: | 40541176 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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