Cu (2 +) ¦Â-amyloid Protein Neurotoxicity And Aggregation State Of The In Vitro Experimental Study

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by irreversible cognitive and physical deterioration, is one of the most common forms of dementia. AD becomes increasingly common with ageing. The etiology of AD remains unknown, and no treatment is available for reversing or stabilizing this disease under the current conditions. Mounting evidence suggests that the key event in the pathogenesis of AD is the abnormal production, aggregation and deposition of amyloid-β (Aβ) peptide, leading to the formation of senile plaque (SP). Aβ is a proteolytic fragment of 39-42 amino acid residues derived from amyloid precursor protein (APP). Two species of most interest are a 40-amino acid Aβ peptide (Aβ₄₀) and a 42-amino acid Aβ peptide (Aβ₄₂).Aberrant high level of copper was found in the senile plaque, suggests copper may play a role in the pathogenesis of AD. The consequent abnormal decoration of Aβ with Cu²⁺ leads to two principal abnormal reactions: redox activity leading to H₂O₂ production and Aβ aggregation. There is a growing body of evidence supports a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products in AD brains. We coincubated VC or VE with Aβ or Aβ/Cu²⁺ complexes in the neuronal cell culture, and the results indicate that both VC and VE could significantly attenuated the cytotoxicity induced by Aβ, but not wholly abolished, suggesting other mechanisms may involve in the pathematology of AD.Despite an increasing body of evidence to link Cu²⁺ with Aβ, the precise coordination geometry and the residues involved in Cu²⁺ ligation are still in dispute. Our results suggest that His6, His13 and His14 are the most potential amino acids responsible for the Aβ-Cu²⁺ binding. Whether Tyr10 in Aβ is involved in copper binding is unknown. Results obtained from cell cultures implicate that Met35 plays a key role in Aβ induced cytotoxicity, but methionine is not involved in copper binding process.To elucidate the effects of copper on the structure and detailed composition of Aβ plaque, circular dichroism (CD), fluorescence spectroscopy and UV spectroscopy were employed. The results indicate a comparatively low density of β-aggregation content in the presence of copperor not, .soluble Aβ oligomers may further form amorphous deposits. In all, our results suggest a negative correlation between the density of βfibril and Aβ-induced oxidative damage and neurotoxicity, but alternatively soluble Aβ oligomers may be the prime criminal of numerous neuronal cell deaths in AD brain.