A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis DOI Creative Commons
Stefan Wendt,

Ada J. Lin,

Sarah N. Ebert

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: April 24, 2025

Abstract Background Alzheimer’s disease (AD) is characterized by progressive amyloid beta (Aβ) deposition in the brain, with eventual widespread neurodegeneration. While cell-specific molecular signature of end-stage AD reasonably well through autopsy material, less known about pathways human brain involved earliest exposure to Aβ. Human model systems that not only replicate pathological features but also transcriptional landscape neurons, astrocytes and microglia are crucial for understanding mechanisms identifying novel therapeutic targets. Methods In this study, we used a 3D iPSC-derived neurosphere explore how resident their interplay modified chronic amyloidosis induced over 3–5 weeks supplementing media synthetic Aβ1 - 42 oligomers. Neurospheres under Aβ were grown or without investigate functional roles microglia. Neuronal activity oxidative stress monitored using genetically encoded indicators, including GCaMP6f roGFP1, respectively. Single nuclei RNA sequencing (snRNA-seq) was performed profile driven changes neurons astrocytes, providing comprehensive analysis cellular responses. Results Microglia efficiently phagocytosed inside neurospheres significantly reduced neurotoxicity, mitigating amyloidosis-induced neurodegeneration following different times The neuroprotective effects conferred presence associated unique gene expression profiles several AD-associated genes such as APOE . These findings reveal can directly alter AD. Conclusions Our culture system reveals may be essential responses pathogenesis. act key drivers Aβ-dependent suggesting critical regulating brain. This novel, characterized, vitro platform offers opportunities study modelling aspects tool will help identify new targets, accelerating transition from discovery clinical applications.

Language: Английский

Neural stem cell quiescence and activation dynamics are regulated by feedback input from their progeny under homeostatic and regenerative conditions DOI
Alina Marymonchyk,

Raquel Rodríguez-Aller,

Ashleigh Willis

et al.

Cell stem cell, Journal Year: 2025, Volume and Issue: 32(3), P. 445 - 462.e9

Published: Feb. 6, 2025

Language: Английский

Citations

1
A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis DOI Creative Commons
Stefan Wendt,

Ada J. Lin,

Sarah N. Ebert

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: April 24, 2025

Abstract Background Alzheimer’s disease (AD) is characterized by progressive amyloid beta (Aβ) deposition in the brain, with eventual widespread neurodegeneration. While cell-specific molecular signature of end-stage AD reasonably well through autopsy material, less known about pathways human brain involved earliest exposure to Aβ. Human model systems that not only replicate pathological features but also transcriptional landscape neurons, astrocytes and microglia are crucial for understanding mechanisms identifying novel therapeutic targets. Methods In this study, we used a 3D iPSC-derived neurosphere explore how resident their interplay modified chronic amyloidosis induced over 3–5 weeks supplementing media synthetic Aβ1 - 42 oligomers. Neurospheres under Aβ were grown or without investigate functional roles microglia. Neuronal activity oxidative stress monitored using genetically encoded indicators, including GCaMP6f roGFP1, respectively. Single nuclei RNA sequencing (snRNA-seq) was performed profile driven changes neurons astrocytes, providing comprehensive analysis cellular responses. Results Microglia efficiently phagocytosed inside neurospheres significantly reduced neurotoxicity, mitigating amyloidosis-induced neurodegeneration following different times The neuroprotective effects conferred presence associated unique gene expression profiles several AD-associated genes such as APOE . These findings reveal can directly alter AD. Conclusions Our culture system reveals may be essential responses pathogenesis. act key drivers Aβ-dependent suggesting critical regulating brain. This novel, characterized, vitro platform offers opportunities study modelling aspects tool will help identify new targets, accelerating transition from discovery clinical applications.

Language: Английский

Citations

0