title: Synergistic interactions between Alzheimer's Aβ40 and Aβ42 on the surface of primary neurons revealed by single molecule microscopy.
abstract: Two amyloid-β peptides (Aβ40 and Aβ42) feature prominently in the extracellular brain deposits associated with Alzheimer's disease. While Aβ40 is the prevalent form in the cerebrospinal fluid, the fraction of Aβ42 increases in the amyloid deposits over the course of disease development. The low in vivo concentration (pM-nM) and metastable nature of Aβ oligomers have made identification of their size, composition, cellular binding sites and mechanism of action challenging and elusive. Furthermore, recent studies have suggested that synergistic effects between Aβ40 and Aβ42 alter both the formation and stability of various peptide oligomers as well as their cytotoxicity. These studies often utilized Aβ oligomers that were prepared in solution and at μM peptide concentrations. The current work was performed using physiological Aβ concentrations and single-molecule microscopy to follow peptide binding and association on primary cultured neurons. When the cells were exposed to a 1:1 mixture of nM Aβ40:Aβ42, significantly larger membrane-bound oligomers developed compared to those formed from either peptide alone. Fluorescence resonance energy transfer experiments at the single molecule level reveal that these larger oligomers contained both Aβ40 and Aβ42, but that the growth of these oligomers was predominantly by addition of Aβ42. Both pure peptides form very few oligomers larger than dimers, but either membrane bound Aβ40/42 complex, or Aβ40, bind Aβ42 to form increasingly larger oligomers. These findings may explain how Aβ42-dominant oligomers, suspected of being more cytotoxic, develop on the neuronal membrane under physiological conditions.
authors: Department of Biophysics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Chun-Chieh
authors: CC
authors: Chang
authors: John Christian
authors: JC
authors: Althaus
authors: Cynthia J L
authors: CJ
authors: Carruthers
authors: Michael A
authors: MA
authors: Sutton
authors: Duncan G
authors: DG
authors: Steel
authors: Ari
authors: A
authors: Gafni
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D008853:Microscopy; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats; D013499:Surface Properties; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)