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Cited by 25Alzheimer's disease research and treatmentsGlycosylation and Glycoproteins ResearchDementia and Cognitive Impairment Research

Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aβ interaction and Aβ fibrillation

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Moon, Hee-Jung, Haroutunian, Vahram, Zhao, Liqin·2022·Neurobiology of Disease
DOI 10.1016/j.nbd.2022.105631PMC PMC9809161
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Abstract

The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer''s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and Aβ peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the Aβ17-24 region of Aβ and promoted Aβ fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in Aβ pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and Aβ and ultimately the slower rate of brain Aβ deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.

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Authors
Moon, H.-J., Haroutunian, V., & Zhao, L.
Affiliations
  • University of Kansas (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Zhao, Liqin
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2022-03
Volume
164
Pages
105631
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2022.105631
PMC
PMC9809161
OpenAlex
W4205898113
Cited by
25
References
15
Citations by year
2026: 6 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 2
FWCI
2.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • KU ScholarWorks (The University of Kansas) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01AG061038, R21AG059177)
  • University of Kansas
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E isoforms, sialylation, sialic acid, APOE2, amyloid-beta, amyloid fibril formation, Alzheimer's disease, post-translational modification, APOE genotype
MeSH terms
Alzheimer Disease, Amyloid, Apolipoproteins E, Brain, Humans, Amyloid beta-Peptides, N-Acetylneuraminic Acid, Protein Isoforms

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