Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease
Open accessAbstract
ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer’s disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. We found that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome, in rodents completely reverses the ApoE4-induced recycling block of the ApoE receptor Apoer2/Lrp8 and the AMPA- and NMDA-type glutamate receptors that are regulated by, and co-endocytosed in a complex with, Apoer2. Moreover, NHE6 inhibition restores the Reelin-mediated modulation of excitatory synapses that is impaired by ApoE4. Our findings suggest a novel potential approach for the prevention of late-onset AD.
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Previous reports have revealed differential activation of APOE receptors by APOE variants.
“Previous reports have revealed differential activation of APOE receptors by APOE variants, potentially explaining the differential biological impact of these variants7–9.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [9]
APOE4 has been observed to exhibit enhanced receptor binding and/or signaling.
“In contrast, APOE4 has been observed to exhibit enhanced receptor binding and/or signaling9,34.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [9]
ApoE4 can greatly inhibit the recycling of apoER2 to the cell surface and thereby severely impair Reelin signaling in neurons.
“apoE4 can greatly inhibit the recycling of apoER2 to the cell surface and thereby severely impair Reelin signaling in neurons”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Xian et al 2018
APOE4 affects the endosomal-lysosomal pathway and the APOE4 induced recycling block can be rescued by decreasing pH.
“APOE4 affects, however, the endosomal-lysosomal pathway (Nuriel et al, 2017) and the APOE4 induced recycling block can be rescued by decreasing pH (Xian et al, 2018).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Xian et al, 2018
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NHE6-driven endosome-autophagy axis confers proteasome inhibitor resistance in multiple myeloma
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ALBAYRAK, İ. G. (2026) · Akademisyen Kitabevi eBooks · doi:10.37609/akya.4278
Mandlik, D. S., & Mandlik, S. K. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103384
Emerging therapeutic strategies to target APOE4 in Alzheimer's disease
Jiang, W. I., 王冰莹, & Ma, D. K. (2026) · FEBS Journal · doi:10.1111/febs.70759
- Authors
- Xian, X., Pohlkamp, T., Durakoglugil, M. S., Wong, C. H., Beck, J. K., Lane-Donovan, C., Plattner, F., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Jkb Consult Inc SPRL, Brussels, Belgium
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
- Corresponding author
- Xian, Xunde
- Herz, Joachim
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-10-30
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6261251
- OpenAlex
- W2899406479
- Cited by
- 98
- References
- 83
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 22 · 2023: 8 · 2022: 14 · 2021: 10 · 2020: 12 · 2019: 7
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R37 HL63762, R01 NS108115, R01 NS093382, RF1 AG053391)
- BrightFocus Foundation (A2016396S)
- Bluefield Project
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- APOE ε4, Alzheimer's disease, late-onset Alzheimer's disease, NHE6, AMPA receptors, NMDA receptor, reelin, excitatory synapses, disease prevention
- MeSH terms
- Reelin Protein, Alzheimer Disease, Animals, Disease Models, Animal, Genotype, Humans, Mice, Inbred C57BL, Endosomes, Rats, Sprague-Dawley, Receptors, Glutamate, Sodium-Hydrogen Exchangers, LDL-Receptor Related Proteins, Apolipoprotein E4, HEK293 Cells
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