The DOI matches its Crossref record; 85 of the 87 references it cites were found in a registry or an index.
A Synthetic Peptide Blocking the Apolipoprotein E/β-Amyloid Binding Mitigates β-Amyloid Toxicity and Fibril Formation in Vitro and Reduces β-Amyloid Plaques in Transgenic Mice
Open accessAbstract
Alzheimer's disease (AD) is associated with accumulation of beta-amyloid (Abeta). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Abeta, promoting its conformational transformation from soluble Abeta into toxic aggregates. We determined if blocking the apoE/Abeta interaction reduces Abeta load in transgenic (Tg) AD mice. The binding site of apoE on Abeta corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Abeta12-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Abeta12-28P competitively blocks binding of full-length Abeta to apoE (IC50 = 36.7 nmol). Furthermore, Abeta12-28P reduces Abeta fibrillogenesis in the presence of apoE, and Abeta/apoE toxicity in cell culture. Abeta12-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Abeta deposition. Tg mice treated with Abeta12-28P for 1 month had a 63.3% reduction in Abeta load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Abeta were not detected in sera of treated mice; therefore the observed therapeutic effect of Abeta12-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Abeta and its pathological chaperones may be beneficial for treatment of beta-amyloid deposition in AD.
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“The ApoE/Ab binding was blocked with Ab12-28P, which is a nontoxic, synthetic peptide modified for increased blood-brain-barrier (BBB) permeability and extended serum half-life.16”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [16]
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“As previously reported, the toxicity of Aβ at micromolar concentration was a potential stumbling block in a recent study.18”
From Amyloid Plaque Imaging with a Targeted MRI Contrast Agent in a Transgenic Mouse Model of Alzheimer’s Disease (2022) · cites this paper as [18]
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“To exert its promoting effect on Aβ aggregation and brain deposition, apoE directly interacts with Aβ, binding to its amino-acid residues 12–28 [11,12].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [12]
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“Ab12-28P is a nontoxic synthetic peptide that was modified for in vivo application, and its BBB permeability was previously evaluated and reported.16”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [16]
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Metadata
- Authors
- Sadowski, M., Pankiewicz, J., Scholtzova, H., Ripellino, J. A., Li, Y., Schmidt, S. D., Mathews, P. M., Fryer, J. D., Holtzman, D. M., Sigurdsson, E. M., & Wisniewski, T.
- Affiliations
- New York University (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Washington University in St. Louis (US)
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 165
- Issue
- 3
- Pages
- 937-948
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1618605
- OpenAlex
- W2164642027
- Cited by
- 154
- References
- 87
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 9 · 2013: 8 · 2012: 10
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG15408, AG20747, AG13956)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- Alzheimer's disease, amyloid-beta, apolipoprotein E, APOE ε4, peptide antagonists, amyloid fibril formation, amyloid plaques, transgenic mice, blood-brain barrier permeability, amyloid deposition
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Binding Sites, Blood-Brain Barrier, Brain, Competitive Bidding, Female, Half-Life, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neuroblastoma, Peptide Fragments, Protein Binding, Tumor Cells, Cultured, Amyloid beta-Peptides, Mice, Knockout, Mice, Presenilin-1
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