title: A2T and A2V Aβ peptides exhibit different aggregation kinetics, primary nucleation, morphology, structure, and LTP inhibition.
abstract: The histopathological hallmark of Alzheimer's disease (AD) is the aggregation and accumulation of the amyloid beta peptide (Aβ) into misfolded oligomers and fibrils. Here we examine the biophysical properties of a protective Aβ variant against AD, A2T, and a causative mutation, A2T, along with the wild type (WT) peptide. The main finding here is that the A2V native monomer is more stable than both A2T and WT, and this manifests itself in different biophysical behaviors: the kinetics of aggregation, the initial monomer conversion to an aggregation prone state (primary nucleation), the abundances of oligomers, and extended conformations. Aggregation reaction modeling of the conversion kinetics from native monomers to fibrils predicts the enhanced stability of the A2V monomer, while ion mobility spectrometry-mass spectrometry measures this directly confirming earlier predictions. Additionally, unique morphologies of the A2T aggregates are observed using atomic force microscopy, providing a basis for the reduction in long term potentiation inhibition of hippocampal cells for A2T compared with A2V and the wild type (WT) peptide. The stability difference of the A2V monomer and the difference in aggregate morphology for A2T (both compared with WT) are offered as alternate explanations for their pathological effects.
authors.affiliation: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, 12180.
authors.forename: Brian
authors.initials: B
authors.lastname: Murray
authors.affiliation: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, 12180.
authors.forename: Mirco
authors.initials: M
authors.lastname: Sorci
authors.affiliation: Department of Mathematical Sciences, Rensselaer Polytechnic Institute, Troy, New York, 12180.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenthal
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, New York, 12222.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippens
authors.affiliation: Department of Mathematical Sciences, Rensselaer Polytechnic Institute, Troy, New York, 12180.
authors.forename: David
authors.initials: D
authors.lastname: Isaacson
authors.affiliation: Soft Matter Theory and Simulations Group, Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, 10598.
authors.forename: Payel
authors.initials: P
authors.lastname: Das
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, New York, 12222.
authors.forename: Daniele
authors.initials: D
authors.lastname: Fabris
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, 12180.
authors.forename: Georges
authors.initials: G
authors.lastname: Belfort
mesh_terms: D000409:Alanine / Q000737:chemistry*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018625:Microscopy, Atomic Force; D008867:Microtomy; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D066329:Protein Aggregates; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D055550:Protein Stability; D013912:Threonine / Q000737:chemistry*; D014633:Valine / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D013912:Threonine; D014633:Valine; D000409:Alanine
keywords: Alzheimer's disease (AD); abeta A2T and A2V; abeta oligomers; amyloid; protective mutation