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Related Experiment Video

Updated: May 26, 2025

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An efficient, non-viral arrayed CRISPR screening platform for iPSC-derived myeloid and microglia models.

Sonja Meier1, Anne Sofie Gry Larsen2, Florian Wanke1

  • 1Pharma Research and Early Development, Neuroscience and Rare Diseases, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

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|February 21, 2025
PubMed
Summary

Researchers used CRISPR-Cas9 gene editing to study lipid handling in human microglia. They found the mTORC1 pathway is crucial for lipid storage, impacting Alzheimer's disease and neuroinflammation research.

Keywords:
APOECRISPR-Cas9 gene editingarrayed genetic screeningiPSC-derived microglialipid accumulationlipid droplet screenlipid metabolismlipid regulationlysosomemTORC1

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Lipid metabolism is increasingly recognized as a key factor in neuroinflammation and Alzheimer's disease (AD).
  • Microglia, the brain's immune cells, play a critical role in AD pathogenesis, and their lipid handling is a significant area of investigation.
  • Understanding the genetic regulators of lipid metabolism in microglia is essential for developing novel therapeutic strategies for AD.

Purpose of the Study:

  • To investigate lipid handling pathways in human induced pluripotent stem cell (iPSC)-derived microglia using a CRISPR-Cas9 arrayed screen.
  • To identify key regulators of lipid droplet formation, particularly those dependent on Apolipoprotein E (APOE).
  • To explore the role of the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway in microglial lipid storage.

Main Methods:

  • Development of a CRISPR-Cas9 arrayed screening platform for genetic perturbations in iPSC-derived myeloid cells.
  • Establishment of a robust nucleofection method for delivering CRISPR-Cas9 ribonucleoprotein complexes.
  • Performance of a targeted screen to identify regulators of APOE-dependent lipid droplet formation.

Main Results:

  • Identification of the mTORC1 signaling pathway as a critical modulator of lipid storage in microglia.
  • Demonstration of mTORC1's role in both APOE3 and APOE knockout microglial lipid handling.
  • Validation of CRISPR-Cas9 technology for functional genomic studies in iPSC-derived microglia.

Conclusions:

  • The mTORC1 pathway is a key regulator of lipid storage in human microglia, with implications for AD.
  • CRISPR-Cas9 screening is a powerful tool for dissecting lipid metabolism pathways in disease-relevant cellular models.
  • This study provides a foundation for further research into lipid dysregulation in neuroinflammation and Alzheimer's disease.