Location and conformation of amyloid β(25-35) peptide and its sequence-shuffled peptides within membranes: Implications for aggregation and toxicity in PC12 cells

Hui Hsu Gavin Tsai, Jian Bin Lee, Yuan Ci Shih, Lei Wan, Fa Kuen Shieh, Chin Yu Chen

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Extracellular deposits of amyloid β (Aβ) aggregates in the brain is the hallmark of Alzheimer's disease. We present the configurations (location and conformation) and the interfacial folding and membrane insertion mechanisms of Aβ fragments, wild-type Aβ(25-35), Aβ(35-25), and a sequence-shuffled peptide [Aβ(25-35)-shuffled] from Aβ(25-35) within membranes by replica-exchange molecular dynamics simulations. Although these peptides have the same amino acid composition, simulations show they have distinct locations and conformations within membranes. Moreover, our in vitro experiments show that these peptides have distinct neurotoxicities. We rationalize the distinct neurotoxicities of these peptides in terms of their simulated locations and conformations in membranes. This work provides another view that complements the general hydrophobicity-toxicity views, to better explain the neurotoxicity of Aβ peptides. Rates of aggregation: Multiple lines of evidence implicate amyloid β peptide as a causative agent in the etiology of Alzheimer's disease. The location and conformation of the peptide within the membrane affects its neurotoxicity. If a peptide is deeply inserted into the membrane, it diffuses slowly because of the membrane matrix. Such slowly diffusing peptides have a lower aggregation rate in the membrane and thus lower toxicity; rapid aggregation yields higher toxicity.

Original languageEnglish
Pages (from-to)1002-1011
Number of pages10
JournalChemMedChem
Volume9
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • aggregation
  • amyloid β peptides
  • folding
  • molecular dynamics
  • neurotoxicity

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