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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 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 miBrain. Combinatorial experiments revealed that lipid-droplet formation in APOE4 astrocytes impairs the degradation of α-²õ²â²Ô³Ü³¦±ô±ð¾±²Ô 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 -mediated pathologies, opening therapeutic opportunities.