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Cited by 333Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease

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Evans, K C, Berger, E P, Cho, C G, Weisgraber, K H, Lansbury, P T·1995·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.92.3.763PMC PMC42700
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Abstract

The apolipoprotein E4 (APOE4) allele is associated with an early age of onset of the nonfamilial form of Alzheimer disease (AD) and with increased beta protein amyloid deposition in the brain. These two observations may both arise from an effect of the apoE family of proteins on the rate of in vivo amyloidogenesis. We report here that apoE3, the common apoE isoform, is an in vitro amyloid nucleation inhibitor at physiological concentrations. A significant delay in the onset of amyloid fibril formation by the beta-amyloid protein of AD (beta 1-40) was observed at a low apoE3 concentration (40 nM), corresponding to an apoE3/beta protein molar ratio of 1:1000. The inhibitory activity of a proteolytic fragment of apoE3, containing the N-terminal 191 amino acids, is comparable to the native protein, whereas the C-terminal fragment has no activity. ApoE4 is equipotent or slightly less potent than apoE3, which may be due to its inability to form a disulfide dimer, since the apoE3 dimer is a significantly more potent nucleation inhibitor than apoE4. Neither apoE3 nor apoE4 inhibits the seeded growth of amyloid or affects the solubility or structure of the amyloid fibrils, indicating that apoE is not a thermodynamic amyloid inhibitor. We propose that the linkage between the APOE4 allele and AD reflects the reduced ability of APOE4 homozygotes to suppress in vivo amyloid formation.

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  • Other studies reported that human apoE isoforms decreased Aβ fibrillogenesis in vitro by interfering with Aβ nucleation.

    “Indeed, other studies reported that human apoE isoforms decreased Aβ fibrillogenesis in vitro by interfering with Aβ nucleation (Beffert and Poirier, 1998; Evans et al., 1995; Webster and Rogers, 1996; Wood et al., 1996).”

    From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Evans et al., 1995

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  1. [5]Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L. & Pericak-Vance, M. A. (1993) Science 261, 921–923.
  2. [7]Štrittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L.-M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 8098–8102.
  3. [13]Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 9649–9653.
  4. [17]Strittmatter, W. J., Saunders, A. M., Schmechel, D., PericakVance, M., Enghild, J., Salvesen, G. S. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 1977–1981.
  5. [20]Horowitz, J. (1992) Proc. Natl. Acad. Sci. USA 89, 10449–10453.

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Authors
Evans, K. C., Berger, E. P., Cho, C. G., Weisgraber, K. H., & Lansbury, P. T.
Affiliations
  • Massachusetts Institute of Technology (US)
  • University of California, San Francisco (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1995-01-31
Volume
92
Issue
3
Pages
763-767
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.92.3.763
PMC
PMC42700
OpenAlex
W2037800112
Cited by
333
References
5
Citations by year
2026: 3 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 8 · 2013: 4 · 2012: 13
FWCI
17.38
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • Eli Lilly and Company
  • Ariad Pharmaceuticals
  • Massachusetts Institute of Technology
  • National Institutes of Health
  • Genentech
  • National Institute on Aging (R01AG008470, AG 08470)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
apolipoprotein E, APOE ε4, APOE3, Aβ40, amyloid fibril formation, Alzheimer's disease, disulfide dimer, proteolytic fragments, amyloid seeding
MeSH terms
Alzheimer Disease, Apolipoproteins E, Humans, Kinetics, Peptide Fragments, Protein Conformation, Thermodynamics, Amyloid beta-Peptides, Apolipoprotein E3, Apolipoprotein E4

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