Apolipoprotein A-I Directly Interacts with Amyloid Precursor Protein and Inhibits Aβ Aggregation and Toxicity
Abstract
Amyloid precursor protein (APP) is the source of the neurotoxic amyloid beta (Abeta) peptide associated with Alzheimer's disease. Apolipoprotein A-I (apoA-I), a constituent of high-density lipoprotein complexes, was identified by a yeast two-hybrid system as a strong and specific binding partner of full-length APP (APPfl). This association between apoA-I and APPfl was localized to the extracellular domain of APP (APPextra). Furthermore, the interaction between apoA-I and APPfl was confirmed by coprecipitation using recombinant epitope-tagged APPextra and purified apoA-I. Several functional domains have been identified in APPextra, and we focused on a possible interaction between apoA-1 and the pathologically important Abeta peptide, because APPextra contains the nontransmembrane domain of Abeta. The binding between apoA-I and Abeta was saturable (K(d) = 6 nM), specific, and reversible. APPextra also competed with apoA-I for binding to Abeta. Direct evidence for this interaction was obtained by the formation of an SDS-resistant Abeta-apoA-I complex in polyacrylamide gels. Competitive experiments with apolipoprotein E (isoforms E2 and E4) showed that apoA-I had a higher binding affinity for Abeta. We also found that apoA-I inhibited the beta-sheet formation of Abeta with a mean inhibitory concentration close to that of alpha2-macroglobulin. Finally, we demonstrated that apoA-I attenuated Abeta-induced cytotoxicity. These results suggest apoA-I binds to at least one extracellula…
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Both apoA-I and apoJ bind to Aβ and prevent Aβ aggregation and toxicity in vitro.
“Both apoA-I and apoJ are known to bind to Aβ and prevent Aβ aggregation and toxicity in vitro (Ghiso et al., 1993; Koldamova et al., 2001; Paula-Lima et al., 2009).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Koldamova et al., 2001
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- Authors
- Koldamova, R. P., Lefterov, I. M., Lefterova, M. I., & Lazo, J. S.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2001-02-27
- Volume
- 40
- Issue
- 12
- Pages
- 3553-3560
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2009692250
- Cited by
- 131
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 2 · 2023: 2 · 2022: 11 · 2021: 8 · 2020: 12 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 8 · 2014: 3 · 2013: 4 · 2012: 9
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 05-133, P50AG005133)
- National Cancer Institute (R01CA043917, CA-43917)
- 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
- apolipoprotein A-I, amyloid precursor protein, amyloid-beta, Alzheimer's disease, protein-protein interaction, amyloid-beta aggregation, β-sheet formation, apolipoprotein E, high-density lipoprotein, neuroprotection
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Extracellular Space, Humans, Oxidation-Reduction, Sodium Dodecyl Sulfate, Tetrazolium Salts, Thiazoles, Amyloid beta-Peptides, Mutagenesis, Site-Directed, Amyloid beta-Protein Precursor, Apolipoprotein A-I, PC12 Cells, Protein Structure, Tertiary, Two-Hybrid System Techniques, Rats
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