Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies.
Dimers of Aβ (amyloid β-protein) are believed to play an important role in Alzheimer's disease. In the absence of sufficient brain-derived dimers, we studied one of the only possible dimers that could be produced in vivo, [Aβ](DiY) (dityrosine cross-linked Aβ). For comparison, we used the Aβ monomer and a design dimer cross-linked by replacement of Ser²⁶ with cystine [AβS26C]₂. We showed that similar to monomers, unaggregated dimers lack appreciable structure and fail to alter long-term potentiation. Importantly, dimers exhibit subtly different structural propensities from monomers and each other, and can self-associate to form larger assemblies. Although [Aβ](DiY) and [AβS26C]₂ have distinct aggregation pathways, they both populate bioactive soluble assemblies for longer durations than Aβ monomers. Our results indicate that the link between Aβ dimers and Alzheimer's disease results from the ability of dimers to further assemble and form synaptotoxic assemblies that persist for long periods of time.
Tiernan T
TT
O'Malley
‡Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9749 AB Groningen, The Netherlands.
Nur Alia
NA
Oktaviani
§Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
Dainan
D
Zhang
∥Department of Physics and Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MA 02139, U.S.A.
Aleksey
A
Lomakin
*Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, U.S.A.
Brian
B
O'Nuallain
¶Department of Biophysical Chemistry, Lund University, SE221 00 Lund, Sweden.
Sara
S
Linse
∥Department of Physics and Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MA 02139, U.S.A.
George B
GB
Benedek
§Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
Michael J
MJ
Rowan
Frans A A
FA
Mulder
*Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, U.S.A.
Dominic M
DM
Walsh
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D019281:Dimerization; D005071:Evoked Potentials / Q000187:drug effects; D006801:Humans; D007276:Injections, Intraventricular; D007700:Kinetics; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D011487:Protein Conformation; D055503:Protein Multimerization; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D012995:Solubility; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40)