Researchers developed a multicellular human brain model called a miBrain to investigate how the APOE4 genetic variant drives neurodegenerative pathology. Their experiments revealed that APOE4 astrocytes suffer from cholesterol dysregulation and endolysosomal dysfunction, preventing them from properly degrading internalized alpha-synuclein. Instead, these impaired astrocytes process the protein into pathogenic seeds that promote neuronal alpha-synuclein aggregation and cell damage. Importantly, treatment with methyl-beta-cyclodextrin successfully reduced cholesterol levels, restored lysosomal function, and decreased pathological phosphorylation in neurons. This study establishes a robust platform for modeling synucleinopathies and highlights cellular cholesterol metabolism as a promising therapeutic target.
References:
Mesentier-Louro L A, Goldman C, Gaese S, et al. Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains[J]. Cell stem cell, 2026, 33(9): 1459-1476. e10.
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