title: Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes.
abstract: 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.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, F.M. Kirby Neurobiology Center, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Soyon
authors.initials: S
authors.lastname: Hong
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Ostaszewski
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Tiernan T
authors.initials: TT
authors.lastname: O'Malley
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Jin
authors.affiliation: National Center for Geriatrics and Gerontology, 474-8522 Aichi, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Bartels
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: dselkoe@rics.bwh.harvard.edu.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D045604:Extracellular Fluid / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000235:genetics / Q000378:metabolism*; D005732:Gangliosides / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005732:Gangliosides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005677:G(M1) Ganglioside; C019403:ganglioside, GD2