Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport

Carriers of the APOE4 (Apolipoprotein E ε4) variant of the APOE gene are subject to several age-related health risks, including Alzheimer's disease (AD). The deficient lipid and cholesterol transport capabilities of the APOE4 protein are one reason for the altered risk profile. In particular, APOE4 carriers are at elevated risk for sporadic Alzheimer's disease (AD). While deposits o misfolded proteins are present in the AD brain, white matter (WM) myelin is also disturbed. As myelin is a lipid- and cholesterol-rich structure, the connection to APOE makes considerable biological sense. To explore the APOE-WM connection, we have analyzed the impact of human APOE4 on oligodendrocytes (OLs) of the mouse both in vivo and in vitro. We find that APOE proteins is enriched in astrocytes but sparse in OL. In human APOE4 (hAPOE4) knockin mice, myelin lipid content is increased but the density of major myelin proteins (MBP, MAG and PLP) is largely unchanged. We also find an unexpected but significant reduction of cell density of the OL lineage (Olig2