An apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42
Open accessAbstract
Apolipoprotein E (apoE) plays a crucial role in lipid transport in circulation and the brain. The apoE4 isoform is a major risk factor for Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have been hypothesized to be involved in the pathogenesis of AD, although the mechanism is not clear. In this study we examined the effect of lipid-free apoE4 on amyloid precursor protein processing and 40-amino-acid Aβ variant and 42-amino-acid Aβ variant levels in human neuroblastoma SK-N-SH cells. We discovered that a specific apoE4 fragment, apoE4[Δ(166-299)], can promote the cellular uptake of extracellular 40-amino-acid Aβ variant and 42-amino-acid Aβ variant either generated after amyloid precursor protein transfection or added exogenously. A longer length fragment, apoE4[Δ(186-299)], or full-length apoE4 failed to elicit this effect. ApoE4[Δ(166-299)] effected a 20% reduction of cellular sphingomyelin levels, as well as changes in cellular membrane micro-fluidity. Following uptake, approximately 50% of 42-amino-acid Aβ variant remained within the cell for at least 24 h, and led to increased formation of reactive oxygen species. Overall, our findings suggest a direct link between two early events in the pathogenesis of AD, apoE4 proteolysis and intraneuronal presence of amyloid beta peptide.
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APOE*4 is associated with increased risk and earlier age-at-onset of Alzheimer's disease, while APOE*2 is associated with decreased risk and later age-at-onset compared to APOE*3.
“of which APOE*4 is associated with an increased risk and earlier age-at-onset (AAO) of Alzheimer’s disease (AD), while APOE*2 is associated with decreased risk and later AAO of AD as compared to the wild type APOE*3 [2–6]”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [5]
The background passage labeled Abstract (page unavailable) says that carrying the ε4 allele increases Alzheimer’s disease risk and lowers the age of onset of late-onset disease. It identifies apoE2 and apoE3 as isoforms but does not say that apoE2 reduces risk or delays onset relative to apoE3; that part of the citing sentence is unsupported by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE ε4 has been linked to intraneuronal Aβ accumulation in the human AD brain, and its fragments seem to promote cellular Aβ uptake.
“It has also been linked to intraneuronal Aβ accumulation in the human AD brain [142] and its fragments seem to promote cellular Aβ uptake [143].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [143]
Not all apoE4 forms found in the brains of AD patients are equally bioactive, and specific apoE4 forms may be involved in processes associated with AD pathogenesis.
“These and other findings suggest that not all apoE4 forms found in the brains of AD patients are equally bioactive and that specific apoE4 forms may be involved in processes associated with AD pathogenesis (10, 14 -17).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [10]
A specific apoE4 fragment can promote the uptake and intracellular accumulation of Aβ42 and lead to increased formation of reactive oxygen species in neuroblastoma cells.
“We have demonstrated previously that a specific apoE4 fragment can promote the uptake and intracellular accumulation of A42 and lead to increased formation of reactive oxygen species in neuroblastoma cells, two events that are considered to be early events in the pathogenesis process of AD (10).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [10]
The single-amino acid L28P mutation gives apoE4 the ability to promote the intracellular accumulation of amyloid beta 42.
“More importantly this single-amino acid mutation gives apoE4 the ability to promote the intracellular accumulation of A42, a function that has also been found previously in a heavily truncated apoE4 variant, apoE4[(⌬(166 -299)] (10)”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [10]
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Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
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“It has also been linked to intraneuronal Aβ accumulation in the human AD brain [142] and its fragments seem to promote cellular Aβ uptake [143].”
BackgroundArgyri, L., Dafnis, I., Theodossiou, T. A., Gantz, D., Stratikos, E., & Chroni, A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.538124 · Cited by 30 · see citing works
Self-citationFan, K., Francis, L., Aslam, M. M., Bedison, M. A., Lawrence, E., Acharya, V., Snitz, B. E., Ganguli, M., DeKosky, S. T., Lopez, O. L., et al. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.11.007 · Cited by 21 · see citing works
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- Authors
- Dafnis, I., Stratikos, E., Tzinia, A., Tsilibary, E. C., Zannis, V. I., & Chroni, A.
- Affiliations
- National Centre of Scientific Research "Demokritos" (GR)
- Boston University (US)
- Corresponding author
- Chroni, Angeliki
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2010-04-20
- Volume
- 115
- Issue
- 4
- Pages
- 873-884
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC2910182
- OpenAlex
- W1798381687
- Cited by
- 41
- References
- 51
- Citations by year
- 2023: 2 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- European Commission
- General Secretariat for Research and Technology
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 68216, R01HL068216)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, amyloid-beta 42, Aβ40, Alzheimer's disease, APP processing, sphingomyelin, membrane fluidity, reactive oxygen species, SK-N-SH cells
- MeSH terms
- Cell Line, Humans, Intracellular Fluid, Peptide Fragments, Amyloid beta-Peptides, Protein Isoforms, Cell Line, Tumor, Apolipoprotein E4
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