Soluble Aβ Oligomers Are Rapidly Sequestered from Brain ISF In Vivo and Bind GM1 Ganglioside on Cellular Membranes
Open accessAbstract
Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics in vivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ₄₂ were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, and its levels correlated with Aβ₄₂, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.
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- Authors
- Hong, S., Ostaszewski, B. L., Yang, T., O’Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- University College Dublin (IE)
- National Center for Geriatrics and Gerontology (JP)
- Corresponding author
- Selkoe, Dennis J.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 82
- Issue
- 2
- Pages
- 308-319
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4129520
- OpenAlex
- W2052707772
- Cited by
- 213
- References
- 72
- Citations by year
- 2026: 18 · 2025: 11 · 2024: 8 · 2023: 14 · 2022: 21 · 2021: 24 · 2020: 21 · 2019: 14 · 2018: 14 · 2017: 17 · 2016: 21 · 2015: 22 · 2014: 8
- FWCI
- 15.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG027443, R01 AG06173, R01AG006173, P01AG036694)
- Yale Center for Clinical Investigation, Yale School of Medicine
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- soluble amyloid-beta oligomers, GM1 ganglioside, brain interstitial fluid, membrane binding, sialic acid, long-term potentiation, hippocampus, Alzheimer's disease, amyloid-beta 42, synaptotoxicity, membrane dysfunction
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Brain, Cell Membrane, Dose-Response Relationship, Drug, Embryo, Mammalian, G(M1) Ganglioside, Gangliosides, Hippocampus, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Extracellular Fluid, Mice, In Vitro Techniques
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