Aβ40 Protects Non-toxic Aβ42 Monomer from Aggregation
Abstract
Abeta40 and Abeta42 are the predominant Abeta species in the human body. Toxic Abeta42 oligomers and fibrils are believed to play a key role in causing Alzheimer's disease (AD). However, the role of Abeta40 in AD pathogenesis is not well established. Emerging evidence indicates a protective role for Abeta40 in AD pathogenesis. Although Abeta40 is known to inhibit Abeta42 fibril formation, it is not clear whether the inhibition acts on the non-toxic monomer or acts on the toxic Abeta42 oligomers. In contrast to conventional methods that detect the appearance of fibrils, in our study Abeta42 aggregation was monitored by the decreasing NMR signals from Abeta42 monomers. In addition, differential NMR isotope labelling enabled the selective observation of Abeta42 aggregation in a mixture of Abeta42 and Abeta40. We found Abeta40 monomers inhibit the aggregation of non-toxic Abeta42 monomers, in an Abeta42/Abeta40 ratio-dependent manner. NMR titration revealed that Abeta40 monomers bind to Abeta42 aggregates with higher affinity than Abeta42 monomers. Abeta40 can also release Abeta42 monomers from Abeta42 aggregates. Thus, Abeta40 likely protects Abeta42 monomers by competing for the binding sites on pre-existing Abeta42 aggregates. Combining our data with growing evidence from transgenic mice and human genetics, we propose that Abeta40 plays a critical, protective role in Alzheimer's by inhibiting the aggregation of Abeta42 monomer. Abeta40 itself, a peptide already present in the…
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Almost all previous studies investigating the effect of bifunctional compounds on the neurotoxicity of metal-Aβ species have focused on the less neurotoxic and possibly even anti-amyloidogenic Aβ40 peptide.
“Almost all previous studies investigating the effect of bifunctional compounds on the neurotoxicity of metal-Aβ species have focused on the less neurotoxic and possibly even anti-amyloidogenic Aβ40 peptide.9,97,98”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [98]
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- Authors
- Yan, Y., & Wang, C.
- Affiliations
- Rensselaer Polytechnic Institute (US)
- Corresponding author
- Wang, Chunyu
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 369
- Issue
- 4
- Pages
- 909-916
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2096665275
- Cited by
- 99
- References
- 10
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 9 · 2023: 6 · 2022: 6 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 10 · 2012: 7
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Aβ40, amyloid-beta 42, Alzheimer's disease, amyloid fibril formation, Aβ42 oligomers, NMR titration, peptide binding affinity, Aβ42/Aβ40 ratio, Alzheimer's disease treatment
- MeSH terms
- Alzheimer Disease, Animals, Humans, Peptide Fragments, Amyloid beta-Peptides, Neuroprotective Agents, Nuclear Magnetic Resonance, Biomolecular, Mice
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