TY - JOUR
T1 - Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes
AU - Hong, Soyon
AU - Ostaszewski, Beth L.
AU - Yang, Ting
AU - O'Malley, Tiernan T.
AU - Jin, Ming
AU - Yanagisawa, Katsuhiko
AU - Li, Shaomin
AU - Bartels, Tim
AU - Selkoe, Dennis J.
N1 - Funding Information:
We are very grateful to R. Ledeen (NJMS) for GM2/GD2 synthase KO mice, D. Harris (BU) for PrnP KO mice, R. Sperling (BWH) for human CSF samples, L. Mucke (UCSF) for J20 mice, D.M. Walsh (BWH) for AW8 antibody, and Elan, plc (South San Francisco, CA) for 3D6, 2G3, and 21F12 antibodies. We thank D.R. Podlisny and W.T. Cavanaugh for technical assistance, M.J. LaVoie and T.L. Young-Pearse for critical reading of manuscript, and members of the Selkoe laboratory for helpful comments. Supported by NIH grants R01 AG027443 (D.J.S.), R01 AG06173 (D.J.S.), and PPG P01 AG036694 (Sperling/D.J.S.), a Harvard NeuroDiscovery Center Pre-doctoral Training Fellowship (S.H.), and a Jerome L. Rappaport Fellowship at HMS (S.H.). D.J.S. is a consultant to Elan and a director of Prothena.
PY - 2014/4/16
Y1 - 2014/4/16
N2 - Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics invivo 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, andits 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.
AB - Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics invivo 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, andits 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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U2 - 10.1016/j.neuron.2014.02.027
DO - 10.1016/j.neuron.2014.02.027
M3 - Article
C2 - 24685176
AN - SCOPUS:84899068704
SN - 0896-6273
VL - 82
SP - 308
EP - 319
JO - Neuron
JF - Neuron
IS - 2
ER -