SINGLE-CELL TRANSCRIPTOMICS IDENTIFIES NECROPTOTIC MEG3+ EXCITATORY NEURONS IN AN IPSC MODEL OF ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is the most common form of dementia. Conventional models of AD including post-mortem brain samples and mouse models have key limitations: post-mortem samples cannot capture early changes in AD, while mouse models have limited translatability. In this context, patient-derived induced pluripotent stem cells (iPSCs) offer a powerful platform to identify early AD-linked alterations that may be better targets for therapies tied to the patient’s genetic background.

We used iPSCs from multiple AD donors that were differentiated into neural fates alongside healthy controls. We used scRNA-seq to study their transcriptomes at multiple stages, revealing the expected cell types such as neuroepithelial cells, progenitors, astrocytes, interneurons, and excitatory neurons (EN). Gene set enrichment analysis showed AD-associated changes across multiple cell types. These include cell division, RNA processing, and metabolic pathways such as oxidative phosphorylation and cholesterol metabolism. Moreover, we found an AD-specific cluster of EN marked by the lncRNA MEG3 (MEG3+ EN), previously shown to trigger necroptosis in human neuron xenografts modelling AD. MEG3+ EN also showed significant upregulation of multiple necroptosis-related genes compared to other EN clusters. However, the molecular mechanism of how MEG3 expression triggers necroptosis needs further exploration.

In summary, we found alterations related to AD including cell division, RNA processing, and metabolic shifts. We also found AD-specific ENs that may be undergoing necroptosis. Importantly, capturing these changes in an in vitro human model, allows for diverse approaches to investigate their underlying mechanisms and reveal novel targets to prevent or slow down neurodegeneration.