Journal
JOURNAL OF CELL SCIENCE
Volume 135, Issue 2, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.258687
Keywords
Alzheimer's disease; APOE; APOE4; Chaperone-mediated autophagy; LC3-associated endocytosis
Categories
Funding
- National Institutes of Health (NIH) [1F30AG060704-01A1, T32GM008620, T32AG000096, S10 OD010669, AG016573, NS072453, NS116872, NS090390]
- Hereditary Disease Foundation
- CHDI Foundation
- Lorna Carlin Fellowship
- University of California
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This study found that APOE4 leads to lysosomal dysfunction and dysregulated autophagy, which may contribute to the pathogenesis of AD.
The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and intemalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis. This article has an associated First Person interview with the first author of the paper.
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