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Front Neurosci. 2017 Dec 12;11:702. doi: 10.3389/fnins.2017.00702. eCollection 2017.

The Endosomal-Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo.

Author information

1
Department of Pathology and Cell Biology, Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, Colombia University, New York, NY, United States.
2
Department of Neuroscience and Physiology, New York University Langone Medical Center, New York University, New York, NY, United States.
3
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States.
4
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
5
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, United States.
6
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York University, New York, NY, United States.
7
Neuroscience Institute, New York University Langone Medical Center, New York University, New York, NY, United States.
8
Department of Psychiatry, New York University Langone Medical Center, New York University, New York, NY, United States.
9
Division of Integrative Neuroscience in the Department of Psychiatry, New York State Psychiatric Institute, New York, NY, United States.

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.

KEYWORDS:

APOE; APOE4; Alzheimer's disease; Apolipoprotein E; RNA-seq; endosome; lysosome; transcriptomics

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