Effects of different isoforms of apoE on aggregation of the α‐synuclein protein implicated in Parkinson’s disease
Open accessAbstract
Parkinson's disease is a progressive brain disorder due to the degeneration of dopaminergic neurons in the substantia nigra. The accumulation of aggregated forms of α-synuclein protein into Lewy bodies is one of the characteristic features of this disease although the pathological role of any such protein deposits in causing neurodegeneration remains elusive. Here, the effects of different apolipoprotein E isoforms (apoE2, apoE3, apoE4) on the aggregation of α-synuclein in vitro were examined using thioflavin T assays and also an immunoassay to detect the formation of multimeric forms. Our results revealed that the aggregation of α-synuclein is influenced by apoE concentration. At low concentrations of apoE (<15nM), all of the isoforms were able to increase the aggregation of α-synuclein (50μM), with apoE4 showing the greatest stimulatory effect. This is in contrast to a higher concentration (>15nM) of these isoforms, where a decrease in the aggregation of α-synuclein was noted. The data show that exceptionally low levels of apoE may seed α-syn aggregation, which could potentially lead to the pathogenesis of α-synuclein-induced neurodegeneration. On the other hand, higher levels of apoE could potentially lower the degree of α-synuclein aggregation and confer protection. The differential effects noted with apoE4 could explain why this particular isoform results in an earlier age of onset for Parkinson's disease.
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Biochemical studies indicate that APOE4 increases the seeding potential of α-synuclein.
“Biochemical studies indicate that APOE4 increases the seeding potential of αSyn131,132, and further mouse studies have shown that APOE4 alters the proteolytic processing of αSyn.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [132]
The Results report that low concentrations of apoE4 stimulated α-synuclein aggregation more than the other isoforms. The Discussion treats a seeding mechanism as a possibility, not a demonstrated effect, and notes evidence that complicates it. The study therefore supports increased aggregation under its in vitro conditions, but not a measured increase in seeding potential. (LLM, conf=0.86)
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- D) Percentage of end-stage α-syn aggregation seen in the presence of different apoE isoform concentrations in the immunoassay for multimeric ThT. The α-syn (50 µM) was incubated for 120 h in the presence of each given concentration of apoE. Data show mean +/-SEM (n = 3) percentage aggregation, relative to α-syn alone. Within each defined concentration of apoE, means with different letters are significantly different (Tukey's HSD, p<0.01). Figure 5. Percentage of end-stage α-syn aggregation seen in the presence of different concentrations of apoE. The data presented in Figures 1b, 2b and 3d have been averaged over all three apoE isoforms, and over all three assays. Data are plotted as mean +/-SEM. Across the different concentrations of apoE, means with different letters are significantly different (Tukey's HSD, p<0.01).
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Uddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212 · see citing works
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Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
- Authors
- Emamzadeh, F. N., Aojula, H., McHugh, P. C., & Allsop, D.
- Affiliations
- Lancaster University (GB)
- University of Manchester (GB)
- University of Huddersfield (GB)
- Corresponding author
- Aojula, Harmesh
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 618
- Pages
- 146-151
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2285146712
- Cited by
- 42
- References
- 5
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 4
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- green
- eprints.lancs.ac.uk
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- University of Huddersfield Repository (University of Huddersfield) (acceptedVersion)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Huddersfield Research Portal (University of Huddersfield) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- apolipoprotein E isoforms, alpha-synuclein aggregation, Parkinson's disease, Lewy bodies, APOE ε4, APOE2, APOE3, neurodegeneration, age of onset
- MeSH terms
- Apolipoproteins E, Parkinson Disease, Recombinant Proteins, Protein Isoforms, alpha-Synuclein, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Protein Aggregates
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