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Amyloid ?-peptide 25-35 self-assembly and its inhibition: a model undecapeptide system to gain atomistic and secondary structure details of the Alzheimer's disease process and treatment.

ABSTRACT: Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the ?-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid ?-peptide 25-35 [A?(25-35)]. A?(25-35) was chosen because it is the shortest fragment capable of forming large ?-sheet fibrils and retaining the toxicity of the full length A?(1-40/42) peptides. The conformational transition, that leads to the formation of ?-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker A?(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the A?(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.

SUBMITTER: Naldi M

PROVIDER: S-EPMC3503346 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Amyloid β-peptide 25-35 self-assembly and its inhibition: a model undecapeptide system to gain atomistic and secondary structure details of the Alzheimer's disease process and treatment.

Naldi Marina M Fiori Jessica J Pistolozzi Marco M Drake Alex F AF Bertucci Carlo C Wu Rongliang R Mlynarczyk Krzysztof K Filipek Slawomir S De Simone Angela A Andrisano Vincenza V

ACS chemical neuroscience 20120904 11

Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the β-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid β-peptide 25-35 [Aβ(25-35)]. Aβ(25-35) was chosen because it is the shortest fragment capable of forming large β-sheet fibrils and retaining th ...[more]

PMID: 23173074

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Project description:During early stages of Alzheimer's disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before the accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence, shown by our laboratory and others, points to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. In particular, two potassium channels that control neuronal excitability, G protein-coupled activated inwardly-rectifying potassium channel (GirK), and voltage-gated K channel (KCNQ), have been recently linked to Aβ pathophysiology in the hippocampus. Specifically, by using Aβ25-35, we previously found that GirK conductance is greatly decreased in the hippocampus, and similar effects have also been reported on KCNQ conductance. Thus, in the present study, our goal was to determine the effect of Aβ on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and associated channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, with special focus in potassium channels. For this purpose, we designed a systematic and reliable procedure to analyze mRNA expression by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in hippocampal rat slices incubated with Aβ25-35. We found that: 1) Aβ down-regulated mRNA expression of ionotropic GluN1 and metabotropic mGlu1 glutamate receptor subunits as previously reported in other AD models; 2) Aβ also reduced gene expression levels of GirK2, 3, and 4 subunits, and KCNQ2 and 3 subunits, but did not change expression levels of its associated GABAB and M1 receptors, respectively. Our results provide evidence that Aβ can modulate the expression of these channels which could affect the hippocampal activity balance underlying learning and memory processes impaired in AD.

Dataset Information

Amyloid ?-peptide 25-35 self-assembly and its inhibition: a model undecapeptide system to gain atomistic and secondary structure details of the Alzheimer's disease process and treatment.

Publications

Amyloid β-peptide 25-35 self-assembly and its inhibition: a model undecapeptide system to gain atomistic and secondary structure details of the Alzheimer's disease process and treatment.

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