Stimulus-Based ApoE Alzheimer's Disease Induction Model Using Microglia-Containing Brain Organoids for Drug Discovery

Area of Science:

• Neuroscience
• Stem Cell Biology
• Disease Modeling

Background:

• Alzheimer's Disease (AD) is a progressive neurodegenerative disorder impacting memory and cognition.
• Current animal models for AD research have limitations in translational relevance due to species-specific differences.
• Induced pluripotent stem cell (iPSC)-derived brain organoids offer a promising human-based model system.

Purpose of the Study:

• To develop and characterize a robust, stimulus-based neuroimmune brain organoid model for Alzheimer's Disease.
• To investigate AD-relevant pathological markers, including neuroinflammation, neurodegeneration, and lipid dysregulation.
• To evaluate the potential of small molecules in ameliorating the induced AD-like phenotype.

Main Methods:

• Generation of planar brain organoids from human iPSCs, incorporating neurons, astrocytes, microglia, and vascular cells.
• Induction of an AD-like phenotype through stimuli.
• Comprehensive characterization using proteomic analysis, immunofluorescence, NfL/GFAP release, scRNAseq, bulk RNAseq, and pathway analysis.
• Assessment of therapeutic interventions with small molecules.

Main Results:

• The developed organoid model successfully demonstrated key AD pathologies: neuroinflammation, neurodegeneration, and lipid dysregulation.
• Analysis revealed AD-relevant pathological markers and cellular responses.
• Small molecule treatment was shown to ameliorate the induced neuroinflammation, lipid dysregulation, and neurodegeneration.

Conclusions:

• This inducible human iPSC-derived brain organoid system provides a valuable platform for studying AD pathogenesis.
• The model effectively recapitulates a complex multicellular brain microenvironment relevant to AD.
• This system holds significant potential for accelerating Alzheimer's Disease drug discovery and development.