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Basic Science and Pathogenesis
Christopher Lee1, Stefan Wendt1, Ada J Lin1
1University of British Columbia, Vancouver, BC, Canada.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
This study used human pluripotent stem cell-derived neurospheres to model Alzheimer's disease (AD) and investigate the role of apolipoprotein E (APOE) variants. Results show APOE ε2 offers protection against amyloid-beta-induced neurodegeneration, highlighting its therapeutic potential.
Area of Science:
- Neuroscience
- Genetics
- Stem Cell Biology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder with apolipoprotein E (APOE) gene polymorphism as a key risk factor.
- APOE ε4 allele increases AD risk, while ε2 and ε3 Christchurch mutations offer protection.
- Understanding APOE's role in AD pathogenesis is crucial for developing therapies.
Purpose of the Study:
- To investigate the impact of different apolipoprotein E (APOE) variants on Alzheimer's disease (AD) pathology.
- To validate a human pluripotent stem cell (hiPSC)-derived 3D neurosphere model for studying AD and APOE function.
Main Methods:
- Generated hiPSC-derived neurospheres containing neurons, astrocytes, and microglia with various APOE genotypes (ε2, ε3, ε4, ε3 Christchurch).
- Exposed neurospheres to chronic oligomeric amyloid-beta treatment to induce AD-like pathology.
- Assessed neuronal activity and degeneration in response to amyloid-beta exposure.
Main Results:
- APOE ε2 variant demonstrated delayed decline in neuronal activity compared to ε4 under amyloid-beta stress.
- ApoE expression increased following amyloid-beta treatment.
- Observed resistance patterns mirrored natural AD resistance, with or without microglia.
Conclusions:
- Validated a novel hiPSC-derived neurosphere model for studying AD and APOE.
- Demonstrated differential neuroprotective effects of APOE variants in a human cell-based model.
- The model system shows promise for future AD drug discovery and mechanism studies.
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