Cu (ii)-induced Beta-amyloid Changes In The Structure And Its Role In The Activation Of Microglia,

Alzheimer's disease is a progressive neurodegenerative disorder affecting memory and cognitive functions of brain,which characterized by the declined cognitive abilities and memories.The pathological features of AD include the extracelluar deposition of senile plaques(SPs),the intracellular neurofibrillary tangles(NFTs) and neuron loss.Amyloidβ-peptide(Aβ),which is the major components of senile plaques,is derived from the membrane-bound amyloid precursor protein(APP).In the previous study,researchers focused mainly on the direct neurotoxicity induced by Aβand reported various hypotheses to explain the mechanism behind the toxicity.Recently,evidence has accumulated that theβ-sheet structure formation plays an important role for Aβto become toxic. Additionally,increased Cu²⁺ concentration has been found in the AD brain which implied that Cu²⁺ may participate in the pathophysiology of AD.Researchers has reported that Cu²⁺ could significantly induce theβ-sheet structure formation and theβ-sheet structure is widely accepted as toxic secondary structure of Aβ.Thus, for a long time,Cu²⁺ is regarded as risk factors for the development of AD. However,in recent years,there is report that Cu²⁺ can also be protective as it can induce Aβto precipitate in a non-βaggregation way which is less neurotoxic thanβ- aggregation.In the present study,the effect of Cu²⁺ on Aβaggregation was analyzed by Circular dichroism(CD),Th-T Fluorescence and Sedimentation Assay, The result indicated that besides the tritional toxic function,as previously reported, Cu²⁺ disrupted the already formedβ-sheet structure,moreover,theβ-aggregates was transformed to non-βaggregates by Cu²⁺.Also,Cu²⁺ induced oligomeric Aβto precipitated in a non-aggregation way.From the molecular point of view,there is accumulated evidence suggest the correlation between Cu²⁺ and Aβ,however,it is still a controversial issue about the residues which involved in the chelation to Cu²⁺. After studied with an Aβmutant,^23,6,13,14Aβ_1-40,we suggested that the three histidine residues were involved in the Aβ-Cu interaction process.Up to now,a lot of work has been done to evaluate the nerotoxicity of Aβin different aggregation state.In recent years,the attribution of microglia to AD has roused a lot of interest and accumulated evidence indicates that the microglia activation and the subsequent neuro-inflammation promoted the progress of AD.In the present study,microglia was exposed to oligomefic and fibrillar Aβin the presence and absence of Cu²⁺,the expression of TNF-aand NO were investigated in mRNA level and the subsequent product level.Real-time PCR,ELISA and Griess reagent analysis were adopted in the present study.The result suggest that both oligomeric and fibrillar Aβactivated microglia potentially,and the activation can be inhibited by Cu²⁺.