(1185-B) Generation and characterisation of a panel of human iPSC-derived neurons and microglia carrying early and late onset relevant mutations for Alzheimer’s disease
Monday, February 5, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: Introduction Alzheimer’s disease (AD) is the most common type of dementia, contributing 60-70% of cases, and affecting more than 24 million people worldwide. There are no disease-modifying treatments available and existing drugs only treat the symptoms and not the root cause of the disease. Development of therapies for AD is hampered because less than 10% of findings derived from preclinical animal models can be translated to humans. Patient-derived induced pluripotent stem cells (iPSCs) enable generation of in vitro models that can recapitulate human disease phenotypes. However, conventional human iPSC differentiation protocols are lengthy, inconsistent, and difficult to scale. The lack of genetically matched controls for patient-derived models further complicates the investigation of disease phenotypes. We have developed opti-ox™, a robust iPSC reprogramming technology that overcomes these limitations and enables generation of mature cell types and disease models, at scale. Our objective was to generate a panel of disease model cells in ioGlutamatergic Neurons, ioGABAergic Neurons and ioMicroglia to enable investigation of the most common AD mutations and accelerate drug discovery.
Material and Methods We used CRISPR/Cas-9 gene editing to generate iPSC-derived glutamatergic and GABAergic neurons carrying the mutations APP V717I, APP KM670/671NL and PSEN1 M146L, and microglia carrying the mutations APOE C112R (converts the wild-type APOE3 allele to APOE4) and TREM2 R47H.
Results Characterisation of our AD disease models shows that the expression profiles of key cell-type specific markers are highly similar to their wild type controls. We demonstrate that the ioMicroglia disease models show either reduced or similar phagocytic activity and cytokine responses compared to the wild type control.
Conclusions Using opti-ox technology we have produced a panel of hiPSC-derived Alzheimer’s disease model cells for research and drug discovery. The panel offers an accessible, consistent, and functional system for investigating the impact of the disease mutations in human neuronal and glial cells enabling research into molecular mechanisms and treatments for AD.