Structure-dependent Impairment of Intracellular Apolipoprotein E4 Trafficking and Its Detrimental Effects Are Rescued by Small-molecule Structure Correctors
Open accessAbstract
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4.
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Small molecules that disrupt the interaction between the N- and C-terminal domains of ApoE4, called structure correctors, have been tested and make ApoE4 less prone to fragmentation.
“In this regard, small molecules that disrupt the interaction between the N- and C-terminal domains of ApoE4 protein, also called “structure correctors”, have been tested in such a way that ApoE4 becomes less prone to fragmentation [85].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [85]
The Results section reports testing the structure correctors GIND25 and PH002, which disrupt apoE4 domain interaction, and finding that they rescued impaired intracellular trafficking. The Discussion says apoE4 proteolysis is domain-interaction-dependent, but this paper does not report testing whether the compounds make apoE4 less prone to fragmentation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNSE-apoE4 mice have impairments in learning and memory and a loss of dendritic spines in primary neurons and in the hippocampus and cortex.
“These mice have impairments in learning and memory [50], as well as a loss of dendritic spines in primary neurons and in the hippocampus and cortex [21].”
From Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development (2012) · cites this paper as [21]
The dendritic-spine Results section (page not provided) reports significantly lower spine density in primary hippocampal neurons cultured from NSE-apoE4 mice than from NSE-apoE3 mice. It also refers to spine loss in the brains of transgenic mice, but does not specify loss in the hippocampus and cortex in vivo. The learning-and-memory clause is attached to a different citation and is not judged here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe dendritic spine density of NSE-apoE4 neurons was significantly less than that of either NSE-apoE3 or WT neurons.
“Consistent with previous findings [21], the dendritic spine density of NSE-apoE4 neurons (Figs. 12E and E′) was significantly less than that of either NSE-apoE3 (Figs. 12D and D′) or WT neurons (Figs. 12C and C′).”
From Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development (2012) · cites this paper as [21]
The dendritic-spine development Results section reports significantly lower spine density in hippocampal neurons from NSE-apoE4 mice than in those from NSE-apoE3 mice (Fig. 11). The study does not report a dendritic-spine comparison with WT neurons, so that part of the attributed claim is unsupported by this source. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMultiple small molecules have been designed to correct the conformation of APOE4 so that it resembles that of APOE3 or APOE2.
“Multiple small molecules have been designed to ‘correct’ the conformation of APOE4 so that it resembles that of APOE3 or APOE2 (refs. 213–217)”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [213]
In neurons, apoE4 is associated with neurotoxicity.
“and neurotoxicity [10, 17–19, 34, 35]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [35]
In neurons, apoE4 is associated with decreased neurite outgrowth.
“decreased neurite outgrowth”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [35]
Treating ApoE4-expressing iPSC-derived neurons with PH002 ameliorated the toxic effects induced by ApoE4.
“Additionally, treating ApoE4-expressing iPSC-derived neurons with PH002, another structure corrector, was able to ameliorate the toxic effects induced by this isoform of ApoE, by reducing ApoE4 detrimental effect on neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons [85], increasing the number of GABAergic neurons and reducing P-tau, Aβ40 and Aβ42 levels [86].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [85]
PH002 treatment reduced ApoE4 detrimental effect on neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons.
“Additionally, treating ApoE4-expressing iPSC-derived neurons with PH002, another structure corrector, was able to ameliorate the toxic effects induced by this isoform of ApoE, by reducing ApoE4 detrimental effect on neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons [85], increasing the number of GABAergic neurons and reducing P-tau, Aβ40 and Aβ42 levels [86].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [85]
GIND25, by blocking ApoE4 domain interaction, modifies the ApoE4 protein tertiary structure into an ApoE3-like conformation.
“By blocking ApoE4 domain interaction, GIND25 was then able to modify the protein tertiary structure into an ApoE3-like conformation, which is proposed to underly the ablation of its neurotoxic effects [85].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [85]
In neurons, apoE4 is associated with impaired mitochondrial respiration.
“In neurons, apoE4 is associated with impaired mitochondrial respiration”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [35]
The Abstract and the section on apoE4 trafficking in mouse primary hippocampal neurons report impaired intracellular trafficking, not mitochondrial respiration. Searches for mitochondrial respiration and oxygen consumption found no passage in our copy addressing the claimed respiratory impairment. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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- Authors
- Brodbeck, J., McGuire, J., Liu, Z., Meyer-Franke, A., Balestra, M. E., Jeong, D.-E., Pleiss, M., McComas, C., Hess, F., Witter, D., Peterson, S., Childers, M., Goulet, M., Liverton, N., Hargreaves, R., Freedman, S., Weisgraber, K. H., Mahley, R. W., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Huang, Yadong
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 286
- Issue
- 19
- Pages
- 17217-17226
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3089564
- OpenAlex
- W2143802939
- Cited by
- 113
- References
- 10
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 10 · 2021: 9 · 2020: 10 · 2019: 10 · 2018: 9 · 2017: 4 · 2016: 10 · 2015: 1 · 2014: 6 · 2013: 5 · 2012: 9
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG‐022074)
- National Institute on Aging (P01AG022074)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, apolipoprotein E3, intracellular trafficking, Alzheimer's disease, endoplasmic reticulum, Golgi apparatus, protein immobilization, domain interactions, neurite outgrowth, dendritic spine development, amyloid precursor protein, secretory pathway, FRAP
- MeSH terms
- Alzheimer Disease, Animals, Biological Transport, Cell Line, Endoplasmic Reticulum, Golgi Apparatus, Hippocampus, Humans, Models, Biological, Mutation, Neurons, Amyloid beta-Protein Precursor, Fluorescence Recovery After Photobleaching, Cell Line, Tumor, Mice, Apolipoprotein E4
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