title: Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy.
abstract: One of the primary neuropathological hallmarks of Alzheimer disease is the presence of extracellular amyloid plaques resulting from the aggregation of amyloid-β (Aβ) peptides. The intrinsic disorder of the Aβ peptide drives self-association and progressive reordering of the conformation in solution, and this dynamic distribution of Aβ complicates biophysical studies. This property poses a challenge for understanding the interaction of Aβ with apolipoprotein E (apoE). ApoE plays a pivotal role in the aggregation and clearance of Aβ peptides in the brain, and the ε4 allele of APOE is the most significant known genetic modulator of Alzheimer risk. Understanding the interaction between apoE and Aβ will provide insight into the mechanism by which different apoE isoforms determine Alzheimer disease risk. Here we applied alternating laser excitation fluorescence cross-correlation spectroscopy to observe the single molecule interaction of Aβ with apoE in the hydrated state. The diffusion time of freely diffusing Aβ in the absence of apoE shows significant self-aggregation, whereas in the presence of apoE, binding of the protein results in a more stable complex. These results show that apoE slows down the oligomerization of Aβ in solution and provide direct insight into the process by which apoE influences the deposition and clearance of Aβ peptides in the brain. Furthermore, by developing an approach to remove signals arising from very large Aβ aggregates, we show that real-time single particle observations provide access to information regarding the fraction of apoE bound and the stoichiometry of apoE and Aβ in the complex.
authors: Physical and Life Science Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
authors: Sonny
authors: S
authors: Ly
authors: Robin
authors: R
authors: Altman
authors: Jitka
authors: J
authors: Petrlova
authors: Yu
authors: Y
authors: Lin
authors: Silvia
authors: S
authors: Hilt
authors: Thomas
authors: T
authors: Huser
authors: Ted A
authors: TA
authors: Laurence
authors: John C
authors: JC
authors: Voss
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D020033:Protein Isoforms; D055503:Protein Multimerization; D013050:Spectrometry, Fluorescence
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D020033:Protein Isoforms