Skip to content

Research highlights: Target identification to modulate neuroinflammation in Alzheimer’s disease

By Leonie Krijger

iPSC-derived astrocytes critical in identifying potential targets to modulate neuroinflammation in Alzheimer’s disease

In their August 2022 article “APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-kB activation,” authors Laurie Arnaud et al. show that human astrocytes carrying the main genetic risk for Alzheimer’s disease – apolipoprotein (APOE4) – are especially prone to inflammation. By leveraging human induced pluripotent stem cell (iPSC)-based strategies for various purposes throughout the study, Arnaud’s team demonstrated that TAGLN3 downregulated in the brains of patients with late-onset sporadic Alzheimer’s disease. 

Their findings, developed using iPSC-based models and validation, highlight an APOE-TAGLN3-NF-kB axis regulating neuroinflammation in human astrocytes and reveal TAGLN3 as a molecular target to modulate neuroinflammation, as well as a potential biomarker for Alzheimer’s disease. 

The use of multiple human iPSC lines derived from patients with sporadic Alzheimer’s disease and non-demented controls enabled the team to determine whether carrying the APOEε4 allele can affect inflammatory-associated functions in human astrocytes. These iPSC lines were also critical in measuring TAGLN3 expression and confirming that TAGLN3 downregulation is strongly associated with the APOE4 polymorphism. 

The team used patient-specific iPSCs as a modeling strategy to study the specific action of APOE4 in human cell derivatives. Given that genetic diversity can be present among patient-specific iPSCs and could confuse research processes, the team employed CRISPR technology to filter out such discrepancies. With that control in place, the researchers deployed an experimental paradigm regarding isogenic controls and generated APOE-knockin and APOE-knockout clones from human iPSC lines. The team used the same experimental paradigm in isogenic iPSC-derived astrocytes to evaluate gene-expression changes that were examined elsewhere in the study. 

Since their discovery by Shinya Yamanaka in 2006, iPSCs have become essential for modeling human diseases, drug development, disease screening and individualized regenerative cell therapy. Research projects like this – studies that simply could not have been conducted without the use of iPSCs – occupy an ever more essential place in drug development.

Key takeaways

  • iPSC-based strategies and techniques enabled Arnaud et al. to create a platform for their discovery and rigorous research, which led to potential new avenues for diagnosing and treating Alzheimer’s disease.

  • Through the use of human iPSCs, researchers demonstrated that the protein APOE controls inflammation in human astrocytes by regulating TAGLN3 expression.

  • iPSC-based techniques led the research team to conclude that TAGLN3 downregulates inflammation controls in the brains of patients with Alzheimer’s disease.

References

Cell Reports 40, 111200, August 16, 2022 https://www.cell.com/action/showPdf?pii=S2211-1247%2822%2901017-8