Metastable structures of amyloid diseases
Small peptides derived from correctly folded proteins transform from unfolded peptides into abnormal amyloid fibrils with cross beta-sheet structure in many unrelated human diseases including Alzheimer’s, Parkinson’s, Huntington’s, type II diabetes, and prion spongiform encephalopathy. |
Strong evidence supports the belief that the toxic agents are not fibrils but the small metastable peptide assemblies that nucleate protofibril precursor structures.
Visualizing these structures at higher resolution makes the lifeScan AFM System an important tool to understand mechanisms of neurotoxicity and to develop and monitor therapeutic drugs.
Alzheimer’s disease fibrillogenesis
The amyloid beta 42 (amino acids 1-42) is the most neurotoxic of the Alzheimer’s peptides. We observe different structures of fibrillogenesis under conditions with varied concentration of input monomeric abeta. Low molecular weight (LMW) or high molecular weight (HMW) transition structures preferentially form, dependent on initiating monomer concentrations.
Structures found in ~20 micromolar (left) and 80 micromolar (right) reactions are shown at the same lateral and Z scales for comparison.
Low MW Oligomer Fibrillogenesis
At low monomeric peptide concentrations (~15 to 25 micromolar) during the first three hours of fibrillogenesis, monomers, dimers and tetramers are observed. View details |
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Additional transition structures form, including what we identify as the unit protofibril. |
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High MW Oligomer Fibrillogenesis
At higher concentrations of monomer peptides (25 to 100 micromolar), within one hour different transition structures form. |
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Disc-like assemblies with lateral dimensions and heights greater than found in LMW oligomer fibrillogenesis are likely precursor forms in a different pathway to protofibrils. |
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