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Daphne Quang1, Breanna Dooling1, Rose Summers1

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Area of Science:

  • Neuroscience
  • Genetics
  • Stem Cell Biology

Background:

  • The APOE ε4 allele (APOE4) is a major genetic risk factor for Alzheimer's disease (AD).
  • APOE4 exacerbates AD risk in individuals with Down syndrome (DS-AD).
  • Microglial-apoE interactions are implicated in neuroinflammation and DS-AD progression, representing a therapeutic target.

Purpose of the Study:

  • To investigate the role of APOE4 in DS-AD using human induced pluripotent stem cell (hiPSC)-based microglia-containing cerebral organoids (MCOs).
  • To identify novel drugs that inhibit apoE4-amyloid-beta (Aβ) interactions and may prevent or delay DS-AD phenotypes.

Main Methods:

  • Developed DS-AD models using hiPSC-derived MCOs and cerebral organoids without microglia (COs).
  • Utilized CRISPR-Cas9 to engineer APOE4/4 genotype in DS and isogenic control hiPSC lines.
  • Screened compounds from the Spectrum Collection library for inhibition of apoE4-Aβ interaction and Aβ fibrillization.

Main Results:

  • Microglia in MCOs modulated amyloid plaque deposition and morphology.
  • APOE4/4 MCOs displayed neurodevelopmental/neurodegenerative phenotypes, with reduced organoid size compared to APOE3/3 MCOs.
  • Identified 23 hit compounds inhibiting apoE4-catalyzed Aβ fibrillization; 3 reduced intracellular Aβ neuropathology in iPSC-derived DS neurons.

Conclusions:

  • hiPSC-derived MCOs are effective models for studying APOE4-linked DS-AD.
  • Discovered potential therapeutic compounds that may prevent or delay the onset of DS-AD.