Cholesterol-mediated Lysosomal Dysfunction in APOE4 Astrocytes Promotes α-Synuclein Pathology in miBrains, a Human iPSC-derived Brain Tissue

Genetic factors like APOE4 are known to increase the prevalence and severity of tau, amyloid, and α-synuclein inclusions. However, the human brain is largely inaccessible during this process, limiting our mechanistic understanding.

Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a functional human brain tissue (“miBrain”). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed cell-type-specific transcriptional responses to synuclein pathology. Like the human brain, we found that pathogenic phosphorylation and aggregation of α-synuclein are increased in the APOE4 miBrain.