Abstract
Possession of the ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Although numerous hypotheses have been proposed, the precise cause of this increased AD risk is not yet known. In order to gain a more comprehensive understanding of APOE4's role in AD, we performed RNA-sequencing on an AD-vulnerable vs. an AD-resistant brain region from aged APOE targeted replacement mice. This transcriptomics analysis revealed a significant enrichment of genes involved in endosomal–lysosomal processing, suggesting an APOE4-specific endosomal–lysosomal pathway dysregulation in the brains of APOE4 mice. Further analysis revealed clear differences in the morphology of endosomal–lysosomal compartments, including an age-dependent increase in the number and size of early endosomes in APOE4 mice. These findings directly link the APOE4 genotype to endosomal–lysosomal dysregulation in an in vivo, AD pathology-free setting, which may play a causative role in the increased incidence of AD among APOE4 carriers.
Highlights
Apolipoprotein E (APOE) plays a vital role in the transport of cholesterol and other lipids through the bloodstream, as well as within the brain (Mahley and Rall, 2000; Han, 2004; Holtzman et al, 2012)
In order to investigate the effect of APOE4 expression in an ADvulnerable vs. an Alzheimer’s disease (AD)-resistant brain region, RNA-sequencing was performed on RNA extracted from the entorhinal cortex (EC) and primary visual cortex (PVC) of 14–15 month-old apolipoprotein E (APOE) targeted replacement mice expressing human APOE3/4 (19 males) vs. APOE3/3 (10 males)
Genes Related to Endosomal–Lysosomal System Function Are Upregulated in the EC of Aged APOE3/4 vs. APOE3/3 Mice
Summary
Apolipoprotein E (APOE) plays a vital role in the transport of cholesterol and other lipids through the bloodstream, as well as within the brain (Mahley and Rall, 2000; Han, 2004; Holtzman et al, 2012). APOE4 Dysregulates the Endosomal–Lysosomal System in Vivo Given these observations, it is important to elucidate the full range of effects that APOE4 expression has on the brain in order to identify new mechanisms that might be responsible for the increased AD risk among APOE4 carriers. The EC was utilized as an AD-vulnerable brain region because it is one of the first brain regions to develop AD pathology (Braak and Braak, 1991; Bobinski et al, 1999), and it has been shown to be vulnerable to APOE4-linked morphological changes (Shaw et al, 2007; Rodriguez et al, 2013; DiBattista et al, 2014). The PVC was utilized as an AD-resistant brain region because it is relatively spared in AD (Braak and Braak, 1991; Minoshima et al, 1997; Wang et al, 2010) and it has not been reported to demonstrate any APOE4-linked morphological changes
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