APOE4 astrocytes show cholesterol dysregulation and α-synuclein pathology

APOE4, a genetic factor increases the severity of Alzheimer’s disease.

Researchers developed an iPSC derived  multicellular integrated brain (miBrain) recapitulating α-synuclein pathogenic accumulation seen in carriers of the APOE4 genetic variant. The model integrates neurons, glia, myelin, and cerebrovascular cells into a human miBrain.

They also observed endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 that astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons.

They identified APOE4 astrocytes as key drivers of α-synuclein pathology.

Pharmacological modulation of cholesterol restored disease phenotypes, pointing to cholesterol metabolism as a promising therapeutic target.

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(26)00302-4

https://sciencemission.com/Cholesterol-dysregulation-in-APOE4