Abstract
Amyloid beta peptide (A(3) is cleaved from the amyloid precursor protein (APP) by P and y secretases and is thought to be responsible for the neurodegeneration that causes the dementia and memory loss observed in Alzheimer's disease (AD). In AD, neuronal death is related to the formation of amyloid plaques, which are observed in brain regions that are susceptible to neurodegeneration. Cif' and Fe3+ are found at the core of the plaques, which are formed by Ap peptides in a P-sheet conformation.|Neuronal death has been shown to be the result of membrane permeability, oxidative stress, and apoptosis. Mutations in the APP gene that exacerbate AD symptoms increase the expression of Ap. This is also demonstrated in patients with Down's syndrome, who have trisomy of chromosome 21. The extra copy of chromosome 21, which contains the APP gene, causes APP to be overexpressed, high levels of Ap to be produced, and the manifestation of AD symptoms at 40 years of age. Patients that carry the s4 allele of apolipoprotein E also develop AD symptoms at an earlier age.|The severity of AD symptoms is proportional to the amount of Ap produced in the brain. Experimental evidence also shows that Ab aggregation is proportional to Ap concentration, and that Ab is able to reduce Cu2+ to Cu4 by the oxidation of Met35 to a sulfuramyl radical cation. This radical can transfer to the C“ backbone of Gly29 or Gly33 of Ap. Cu2f speeds Ap aggregation, an effect that is attenuated by the presence of Cu2 chelators. The relationship between Cu2+, Ab aggregation and the induced p conformation requires elucidation. Does Cu2 cause the oxidation of Met35, with the subsequent transfer from Met35 to Gly29 or Gly33 induce the p conformation of Ap and promote aggregation? CD measurements of iV-Ac-AP(25-35)-NI E in the absence or presence of Cu2+, and quantum mechanical calculations on closed and open-shelled Gly dipeptide and Gly-Gly tripeptide models should validate or refute this hypothesis.|The Cu2+ did not induce the P-sheet conformation of Ap in CD experiments. The helical conformation induced by trilluoroethanol (TFE), which has been observed in Ap peptides in hexafluoroisopropanol and membrane vesicles, supports the possible interaction of Ap with the plasma membrane. However, the presence of a Cu radical at a Gly residue did invoke the P-sheet conformation. This did not affect the conformation of neighboring residues, but the conformational stability at the C“ is inversely related to the magnitude of the spin density at the C“. The spin density also dissipated as the distance from the C“ increased, providing rationale for the lack of effect of Ca on the conformation of neighboring residues. Future CD experiments using Ap fragments that include the Cu2+ binding site, which is vital for Cu: reduction, could provide the mechanism by which Cu2+ induces the P-sheet conformation responsible for the Ap toxicity. In turn, mechanisms that attenuate this event without affecting the distribution and the biological function of Ap, can be elucidated.