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P2‐261: ATR‐IR and UV‐VIS studies of the Iowa mutation show an increased rate of beta sheet formation
Author(s) -
Reinsalu Sean,
Peszek Sandra Chimon,
Udad Xavier
Publication year - 2011
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.2011.05.1142
Subject(s) - neurodegeneration , beta sheet , fibril , neurotoxicity , biophysics , chemistry , amyloid (mycology) , protein secondary structure , peptide , congo red , amyloid beta , biochemistry , microbiology and biotechnology , toxicity , biology , medicine , disease , pathology , inorganic chemistry , organic chemistry , adsorption
Background: Synaptic malfunctions and neural death resulting from toxic accumulations of misfolding amyloid proteins is characteristic of neurodegenerative diseases. Deposits of ß-sheet fibrils in the brain are believed to be a commonmechanism among these diseases. Studies of neurotoxicity focus on the formation of these toxic structures in vitro. However, the beta-amyloid peptide 1-40 and 1-42, associated with the cause of Alzheimer’s disease, undergoes various transformation processes resulting in structural changes in the protein shape. Although, the cause of neurodegeneration in Alzheimer’s is often attributed to the formation of toxic ß-sheets, research conductedbyDr.ChimonPeszek founddiffusible ß-sheet intermediates, presenting a similar toxicity as fibrils. These highly unstable morphologies may play an important role in neurodegeneration. Moreover, they provide potential information about the irregular folding process and rate of fibril formation among the various mutations of the ß-amyloid peptide. Many studies attribute neurotoxicity to the “KLVFFA” region, from residues 16-21; however, we chose to concentrate on a shorter sequence, 22-35, in order to study the effect on fibril formation without the “KLVFFA” region. Instead, our research focuses on the role of the hair-pin turn and the salt-bridge attraction between Asp-23 and Lsy-28 to the rate of ß-sheet formation. Methods: Our research is among the first to utilize ATR-IR to identify ß-sheet formation and the secondary conformations of ß-sheet intermediates.We also used UV-Vis to study the concentration of fibrils in situ over the length of our experiment.Results:A single-pointmutation at the hair-pin turn, known as the “Iowa mutation”, Aß1-40 D23N, demonstrates earlier ß-sheet formation in comparison to the Wild Type. This accelerated production of harmful ß-sheet aggregates in the Iowa mutant implicates the mutation of Asp-23 to Asn-23 as a severe transformation resulting in an earlier onset of neurodegeneration. ATR-IR and UV-Vis studies of Aß22-35 confirmed the formation of ß-sheets. Further data from NMR and TEM may help to identify ß-sheet intermediate forms of the Iowa mutation and the structural contribution of this mutation to the increased rate of ß-sheet formation. Uncovering more knowledge about these intermediate structures could have a significant impact on future therapeutic medicines and treatments.