Metal ion-induced aggregation of A beta into insoluble plaques is a centralfactor in Alzheimer's disease.Zn^(2+) is the only physiologically available transition metal ionresponsible for aggregating A beta at pH 7.4.To make it clear that the neurotoxicity ofZn^(2+)-induced aggregation of A beta on neurons is the key to understand A beta mechanism of actionfurther.In this paper,we choose A/?(10-21) as the model fragment to research hippocampal CA1pyramidal neurons.For the first time,we adopt the combination of spectral analysis with patch-clamptechnique for the preliminary study of the mutual relations of Zn^(2+),A beta and ion channel fromthe cell level.The following expounds upon the effects and mode of action of two forms (unaggregatedand aggregated) of A beta(10-21) on hippocampus outward potassium channel three processes(activation,inactivation and reactivation).It also shows the molecular mechanics of AD from thechannel level.These results are significant for the further study of A beta nosogenesis and thedevelopment of new types of target drugs for the treatment of AD.
The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H 13, acting as the anchoring site, and the backbone＇s deprotoned amide nitogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.
Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, cata-lysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.
JIAO Yong & YANG Pin Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, China
The ion channel-like nanotube structure of the oligomers of amyloid β-peptide (Aβ) was first investi-gated by molecular modeling. The results reveal that the hydrogen bond net is one of the key factors to stabilize the structure. The hydrophobicity distribution mode of the side chains is in favor of the structure inserting into the bilayers and forming a hydrophilic pore. The lumen space is under the control of the negative potential,weaker but spreading continuously,to which the cation selectivity attributes; meanwhile,the alternate distribution of the stronger positive and negative potentials makes the electrostatic distribution of the structure framework balance,which is also one of the key factors stabilizing the structure. The results lay the theoretical foundation for illuminating the structure stability and the ion permeability,and give a clue to elucidating the molecular mechanism of Alzheimer's dis-ease (AD) and designing novel drugs to prevent or reverse AD at the root.
