AUTHOR=Nuriel Tal , Peng Katherine Y. , Ashok Archana , Dillman Allissa A. , Figueroa Helen Y. , Apuzzo Justin , Ambat Jayanth , Levy Efrat , Cookson Mark R. , Mathews Paul M. , Duff Karen E. 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=11

YEAR=2017

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2017.00702

DOI=10.3389/fnins.2017.00702

ISSN=1662-453X

ABSTRACT=<p>Possession of the ε4 allele of apolipoprotein E (<italic>APOE</italic>) 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 <italic>APOE4</italic>'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 <italic>APOE4</italic>-specific endosomal–lysosomal pathway dysregulation in the brains of <italic>APOE4</italic> 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 <italic>APOE4</italic> mice. These findings directly link the <italic>APOE4</italic> genotype to endosomal–lysosomal dysregulation in an <italic>in vivo</italic>, AD pathology-free setting, which may play a causative role in the increased incidence of AD among <italic>APOE4</italic> carriers.</p>