Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies
Yuriy Pomeshchik, Oxana Klementieva, Jeovanis Gil, Isak Martinsson, Marita Grønning Hansen, Tessa de Vries, Anna Sancho‐Balsells, Kaspar Russ, Ekaterina Savchenko, Anna Collin, Ana Rita Vaz, Silvia Bagnoli, Benedetta Nacmias, Claire Rampon, Sandro Sorbi, Dora Brites, György Marko‐Varga, Zaal Kokaia, Melinda Rezeli, Gunnar K. Gouras, Laurent Roybon
Abstract
The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.