The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

• Main Authors: Tal Nuriel, Katherine Y. Peng, Archana Ashok, Allissa A. Dillman, Helen Y. Figueroa, Justin Apuzzo, Jayanth Ambat, Efrat Levy, Mark R. Cookson, Paul M. Mathews, Karen E. Duff
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-12-01
• Series: Frontiers in Neuroscience
• Subjects: Apolipoprotein E; APOE; APOE4; endosome; lysosome; Alzheimer's disease
• Online Access: http://journal.frontiersin.org/article/10.3389/fnins.2017.00702/full

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.