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P1‐431: Production of micelle‐like structures during the early stages of Aβ(1–40) and Aβ(1–42) association
Author(s) -
Zagorski Michael G.,
Li Lei,
Hou Liming,
Miller Megan,
Bhaskar Kiran,
Anderson Ver,
Mann Jay,
Lamb Bruce
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1013
Subject(s) - micelle , chemistry , fibril , biophysics , amyloid (mycology) , amyloid fibril , extracellular , peptide , biochemistry , amyloid β , organic chemistry , biology , disease , medicine , inorganic chemistry , pathology , aqueous solution
Background: Alzheimer’s disease (AD) is characterized by the abundance of intraneuronal neurofibrillary tangles and the extracellular deposition of the A peptide into amyloid plaques. The A becomes neurotoxic to cortical cell cultures when aggregated as amyloid-like -sheet structures, A protofibrils, or other soluble aggregates such as ADDLs. Current thinking is that the soluble -sheet aggregates, and not the insoluble amyloid plaques, are the real culprits responsible for AD-associated neuronal death. In this area, there is a dearth of detailed structural information. Methods: Our research work is unique, in that we utilize high-resolution NMR methods to discern the molecular structures of the early-formed A aggregates such as the ADDLs. A major advantage of the NMR approach is that it can provide atomic level aspects of the structures and dynamics in solution that are not available with other low-resolution techniques. Results: Our NMR data demonstrate that the ADDL assemblies have micellelike properties, in which the A hydrophobic C-terminus becomes clustered around the center of the micelle. A peptides containing oxidized methionine-35 disrupt the micelle structure, presumably due to the increased polarity imparted at the C-terminus, and the A (1-42) oligomers induce altered microglial morphology consistent with microglial activation. Conclusions: The importance of the micelle-like properties toward the development of therapeutic compounds to block ADDL formation is discussed.