If you have any problems related to the accessibility of any content (or if you want to request that a specific publication be accessible), please contact (firstname.lastname@example.org). We will work to respond to each request in as timely a manner as possible.
Change in Copper Coordination Environment of the English Mutant of the Amyloid-β Peptide Relative to Wild-type Amyloid-β
AuthorPeck, Kristy Lee
AdvisorShearer, Jason M.
StatisticsView Usage Statistics
The neurodegenerative disorder, Alzheimer's Disease (AD), is the most common cause of senile dementia, or loss of brain function in the elderly population. The development of AD can be attributed to the formation of amyloid-β (Aβ) peptides, which range from 37 to 43 residues in length and result from cleavage of the Amyloid Precursor Protein (APP). One such peptide, Aβ(42) (DAEFR HDSGY EVHHQ KLVFF AEDVG SNKGA IIGLM VGGVV IA), is highly neurotoxic and aggregates readily to form soluble oligomers. Mutations occurring in the N-terminus region of the of the Aβ peptide are known to cause early onset AD, in which a patient develops AD in their early 40's. In one such mutation, known as the English Mutant, the histidine residue at position 6 in the amino acid sequence is replaced with an arginine residue, denoted Aβ(42)H6R. X-ray absorption and EPR spectroscopy were applied to Aβ(42)H6R oligomers in order to probe the coordination environment of Cu(II) and Cu(I). The formation of soluble oligomers was confirmed by GPC, FT-IR and a Thioflavin-T fluorescence binding assay. X-band EPR studies on Aβ(42) H6R Cu(II) oligomers indicate a four-coordinate square planar geometry for Cu(II). When one equivalent of ascorbate was introduced into the complex the Cu center was reduced and the EPR signal disappeared which leads to a hypothesis that the Cu(I) coordination environment is held in a redox inactive linear bis-His geometry. Cu K-edge XAS was carried out on the Aβ(42) H6R oligomers to corroborate the hypothesis of the linear bis-His geometry of Cu(I). The XANES region of Cu(II) bound Aβ(42) H6R was consistent with the EPR study and yielded a mixture of two different four-coordinate geometries with N/O ligation. As the EPR data suggested, the XANES region for Aβ(42) H6R Cu(I) returned a linear bis-His coordination environment. For both the XAS and the EPR spectra, no change was seen in the spectra after exposure to air for several days. This indicated a lack of peptide degradation due to the inert redox activity about the Cu center which was confirmed by HPLC over several days. We see that soluble oligomers of Aβ(42) H6R behave like Aβ monomers and are completely redox inactive which may suggest that an imbalance of metal ion homeostasis in the brain is causative of AD pathogenesis.