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Molecular mechanism of misfolding and aggregation of Aβ(13-23)

Sándor Lovas1, Yuliang Zhang, Junping Yu

  • 1Department of Biomedical Sciences, Creighton University, Omaha, Nebraska 68178, United States. slovas@creighton.edu

The Journal of Physical Chemistry. B
|May 7, 2013
PubMed

Insights

Alzheimer

Area of Science:

  • Biochemistry
  • Neuroscience
  • Biophysics

Background:

  • Amyloid-beta (Aβ) peptide aggregation into amyloid fibrils is a hallmark of Alzheimer's disease.
  • The precise molecular mechanisms driving Aβ misfolding and aggregation remain poorly understood.

Purpose of the Study:

  • To investigate the initial misfolding and dimerization process of the amyloid-beta (Aβ) peptide.
  • To elucidate the molecular interactions and conformational changes involved in Aβ dimer formation.

Main Methods:

  • Utilized Atomic Force Microscopy (AFM) with dynamic force spectroscopy to analyze peptide-dimer interactions.
  • Employed Molecular Dynamics (MD) simulations to model and characterize Aβ monomer and dimer conformations and dynamics.

Main Results:

  • AFM revealed the formation of stable Aβ dimers with a characteristic lifetime of approximately 1 second.
  • MD simulations demonstrated that monomers lose conformational flexibility upon approaching each other, leading to cooperative β-sheet formation in an antiparallel orientation.
  • Identified stabilizing interactions including hydrogen bonds, salt bridges, and side-chain interactions within the Aβ dimer structure.

Conclusions:

  • Aβ peptide misfolding initiates with the loss of conformational flexibility and the formation of stable dimers.
  • These stable dimers are proposed to play a critical role in the subsequent aggregation pathway leading to Alzheimer's disease pathology.

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