Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes

Abstract INTRODUCTION The ε4 allele of the apolipoprotein E ( APOE ) gene is a risk factor for the development of Alzheimer's disease (AD). APOE4 isoform is associated with increased white matter lesions in humans. To identify the underlying mechanisms of white matter impairment associated with APOE4 , we investigated the effects of APOE4 and APOE3 on multiple readouts of the white matter microstructural integrity. METHODS Using magnetic resonance imaging and immunohistochemistry approaches, we analyzed white matter tracts in 5xFAD mice expressing APOE3 (5xFAD; APOE3 ) or APOE4 (5xFAD; APOE4 ). RESULTS APOE4 significantly decreased fractional anisotropy, axial diffusivity, and neurite density index, while increasing radial diffusivity and isotropic volume fraction within major white matter tracts. Myelination was reduced in the corpus callosum of 5xFAD; APOE4 mice. Mechanistically, APOE4 reduced populations of mature and actively myelinating oligodendrocytes. DISCUSSION Our results suggest that a decrease in the number of actively myelinating oligodendrocytes may explain myelin loss, leading to white matter impairments. Highlights A robust neurite orientation dispersion and density imaging (NODDI) approach to study the effect of apolipoprotein E (APOE) isoforms on the white matter in 5xFAD mice. APOE4 reduces neurite density and increases water accumulation in the white matter. APOE4 disrupts structural connectivity and reduces the betweenness centrality. APOE4 decreases the number of actively myelinating oligodendrocytes. A reduction in myelinating oligodendrocyte populations may lead to myelin loss.