Cholesterol-mediated Lysosomal Dysfunction in APOE4 Astrocytes Promotes α-Synuclein Pathology in Human Brain Tissue
Output Details
Description
The pathological hallmark of neurodegenerative disease is the aberrant post-translational modification and aggregation of proteins leading to the formation of insoluble protein inclusions. 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). Like the human brain, we found pathogenic phosphorylation and aggregation of α-Synuclein is increased in the *APOE4* miBrain. Combinatorial experiments revealed that lipid-droplet formation in APOE4 astrocytes impairs the degradation of α-synuclein and leads to a pathogenic transformation that seeds neuronal inclusions of α-Synuclein. Collectively, this study establishes a robust model for investigating protein inclusions in human brain tissue and highlights the role of astrocytes and cholesterol in *APOE4*-mediated pathologies, opening therapeutic opportunities.
Identifier (DOI)
10.1101/2025.02.09.637107
