Zhaofeng Jiang

Copper Enhances Amyloid-β Peptide Neurotoxicity and non β-Aggregation: A Series of Experiments Conducted upon Copper-Bound and Copper-Free Amyloid-β Peptide

Alzheimer’s disease is characterized by the abnormal aggregation of amyloid-β peptide (Aβ) in extracellular deposits known as senile plaques. However, the nature of the toxic Aβ species and its precise mechanism of action remain unclear. Previous reports suggest that the histidine residues are involved in copper–Aβ interaction, by which resulting in the neurotoxicity of Aβ and free radical damage. Here, we employed a mutant Aβ (Aβ H13R) in which a histidine residue was replaced by arginine. Copper facilitated the precipitation of both wild-type and mutant Aβ in the spectrophotometric absorbance assay but suppressed β-structure aggregates according to Thioflavine-T assay. Wild-type Aβ alone is more cytotoxic but produced less amount of H2O2 than AβH13R–copper complexes, suggesting that Aβ–membrane interaction may also implicated in the pathologic progress. Aβ toxicity is in positive correlation to its competence to aggregate despite the aggregation is mainly composed of non-β fibril substances. In short, these findings may provide further evidence on the role of copper in the pathogenesis of Alzheimer’s disease.

Chitosan oligosaccharides protect rat primary hippocampal neurons from oligomeric β-amyloid 1-42-induced neurotoxicity.

β-Amyloid peptide (Aβ), the major component of senile plaques in patients with Alzheimers disease (AD), is believed to facilitate the progressive neurodegeneration that occurs in this disease. Mounting natural compounds are proved to be potential candidates for the prevention and treatment of AD. Chitosan oligosaccharides (COSs), the enzymatic hydrolysates of chitosan, have been reported to possess diverse biological activities. Here we investigated the effect of COSs on oligomeric Aβ-mediated toxicity in rat primary hippocampal neurons. Pretreatment with COSs markedly inhibited cell death induced by Aβ exposure as determined by cell viability assay and lactate dehydrogenase release assay. In parallel, the generation of reactive oxygen species and lipid peroxidation were attenuated by COSs. Furthermore, our results indicated that COSs remarkably prevented Aβ-induced cell apoptosis as manifested by depressing the elevation of Bax/Bcl-2 ratio and caspase-3 activation, suggesting that the neuroprotective effect of COSs could be partially due to apoptosis regulation. In addition, pretreatment with COSs significantly blocked Aβ-induced phosphorylation of c-Jun N-terminal kinase. Taken together, these findings may shed light on the role of COSs as a potential therapeutic agent for AD.

Attenuated cytotoxicity but enhanced βfibril of a mutant amyloid β-peptide with a methionine to cysteine substitution

Amyloid‐β peptide (Aβ), the major constituent of senile plaques in the Alzheimers disease (AD) brain, is the main source of oxidative stress leading to neurodegeneration. The methionine residue in this peptide is reported to be responsible for neurotoxicity. Structurally similar substitution with methionine 35 replaced by cysteine in Aβ40 was synthesized, and this result in enhanced β‐sheet structures according to both circular dichroism (CD) spectra and β‐fibril specific fluorescence assay but attenuated cytotoxicity whether in the presence of copper or not. These findings may provide further evidence on disclosing the connection between amyloid β‐aggregation and Aβ‐induced neurotoxicity.

Treatment with lutein provides neuroprotection in mice subjected to transient cerebral ischemia

Lutein is known to be a nonprovitamin A carotenoid found in broccoli and spinach. The aim of present study was to investigate whether lutein can protect brain against ischemic injury by reducing oxidative stress. Male ICR mice were randomly divided into five experimental groups: model group, sham group, lutein high, middle, and low-dose groups (30, 15, and 7.5 mg/kg). Mice were subjected to a 2-h middle cerebral artery occlusion followed by reperfusion for 22 h. The reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, antioxidant enzyme activities, malondialdehyde (MDA), and the carbonyl content in oxidatively modified proteins in brain tissue were determined with colorimetric method. The 8-hydroxy deoxyguanosine (8-OHdG) expression was measured by immunohistochemistry assay, and the neuron apoptosis was detected by TdT-mediated dUTP nick end labeling assay. Then, the neurological deficit scores were measured at last. Treatment of lutein significantly elevated the ratio of GSH/GSSG as well as activities of superoxide dismutase, glutathione peroxidase, and catalase and obviously decreased the contents of MDA, brain carbonyl, the expression of 8-OHdG, the number of apoptotic cells, and neurological deficit scores. Our results demonstrate that administration of lutein affords strong neuroprotective effect against transient cerebral ischemic injury and that the effect might be associated with its antioxidant property.