Issue Information

Abstract

Front cover 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), sporadic AD in particular. While deposits of misfolded proteins are present in the AD brain, white matter (WM) myelin is also disturbed. 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+) and an abnormal accumulation of OL precursors (Nkx 2.2+), suggesting a disruption of OL differentiation. Our data suggest that APOE4 impairs myelination in the aging brain by interrupting the delivery of astrocyte-derived lipids to the oligodendrocytes. We propose that high myelin turnover and OL exhaustion found in APOE4 carriers is a likely explanation for the APOE-dependent myelin phenotypes of the AD brain. Image content Cholesterol depletion by lovastatin compromises myelin sheet formation (MBP, blue; MAG, green) in mature oligodendrocytes (Olig2, red). Read the full article ‘Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte- derived lipid transport’ by K. K.- S. Mok, S. H.- S. Yeung, G. W.- Y. Cheng, I. W.- T. Ma, R. H.- S. Lee, K. Herrup, K.- H. Tse, (J. Neurochem. 2023, vol.165 (1), pp. 55–75) on doi:10.1111/jnc.15748