Authors
Louise A Mesentier-Louro, Camille Goldman, Sebastian Gaese, Alice Buonfiglioli, Dimitrios Kyriakis, Ashley Harlock, Alain Ndayisaba, Emily R Sartori, Abigail Uchitelev, John F Fullard, Evelyn Hennigan, Donghoon Lee, Braxton R Schuldt, Rikki B Rooklin, Jonathan Barra, Jose Javier Bravo-Cordero, Panos Roussos, Vikram Khurana, Joel W Blanchard
Published in
Cell stem cell. Aug 24, 2026. Epub Aug 24, 2026.
Abstract
The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.
PMID:
42636814
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.
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