Amyloid peptide fibrillogenesis induced by Cu（II） ions is a key event in the pathogenesis of Alzheimer＇s disease. Dendrimers have been found to be active in preventing fibril formation. Therefore, they hold promise...Amyloid peptide fibrillogenesis induced by Cu（II） ions is a key event in the pathogenesis of Alzheimer＇s disease. Dendrimers have been found to be active in preventing fibril formation. Therefore, they hold promise for the treatment of Alzheimer＇s disease. In this study, the fibrillation mechanism of amyloid peptide Aβ 1-40 was studied by adding Cu（II） in the absence and presence of 4th generation poly（propyleneimine） glycodendrimer functionalized with sulfate groups, using dynamic light scattering （DLS）, circular dichroism （CD）, fluorescence, electron paramagnetic resonance （EPR） and molecular modeling （MD）. The glycodendrimer was non-toxic to mHippoE-18 embryonic mouse hippocampal cells, selected as a nerve cell model and decreased the toxicity of peptide aggregates formed after the addition of Cu（II）. The binary systems of Cu（II）-glycodendrimer, Cu（II）-peptide, and glycodendrimer-peptide were first characterized. At the lowest Cu（II）/glycodendrimer molar ratios, Cu（II） was complexed by the internal-dendrimer nitrogen sites. After saturation of these sites, Cu（II） binding with sulfate groups occurred. Stable Cu（II）-peptide complexes formed within 5 min and were responsible for a transition from an α helix to a β-sheet conformation of Aβ 1-40. Glycodendrimer-peptide interactions provoked the stabilization of the a-helix, as demonstrated in the absence of Cu（II） by the Thioflavin T assay, and in the presence of Cu（II） by CD, EPR, and MD. Formation of fibrils is differentially modulated by glycodendrimer and Cu（II） concentrations for a fixed amount of Aβ 1-40. Therefore, this multidisciplinary study facilitated the recognition of optimal experimental conditions that allow the glycodendrimer to avoid the fibril formation induced by Cu（II）.展开更多
Inspired by the intricate eukaryotic cell structure,the spontaneously assembling multicompartments capable of spatiotemporally regulated biomacromolecules transportation is still a challenge.Here,a heterogeneous prote...Inspired by the intricate eukaryotic cell structure,the spontaneously assembling multicompartments capable of spatiotemporally regulated biomacromolecules transportation is still a challenge.Here,a heterogeneous proteinosome-based multicompartment was designed and constructed by combining aqueous two-phase system and Pickering emulsion methods.By loading PEGylated insulin with boronic acid group into the multicompartment and glucose oxidase(GOx)into the innermost microgel domain,a short-or long-term transportation pathway of the loaded insulin was constructed by responding to the concentration of glucose.Moreover,the diminution of dynamic boronic ester bonding,the hindrance of polyethylene oxide micro-chamber,electrostatic interaction and the swelling behavior of hydrogel triggered by GOx/glucose reaction resulted in spatiotemporally controlled multi-pathway transportation mode with the releasing of insulin loaded inside the innermost microgel at high concentration of glucose(10 mg·mL^(-1)).Specially,by incorporating rhodamine B and fluorescein labelled BSA into the multicompartment,the release procedure of the loaded insulin can be monitored by the fluorescence color-change.Overall,a multimode microcompartment is constructed which is then expected to provide a promising platform for further therapeutic protein,gene and drug delivery,as well as towards the design of complicated cell biomimetics.展开更多
文摘Amyloid peptide fibrillogenesis induced by Cu（II） ions is a key event in the pathogenesis of Alzheimer＇s disease. Dendrimers have been found to be active in preventing fibril formation. Therefore, they hold promise for the treatment of Alzheimer＇s disease. In this study, the fibrillation mechanism of amyloid peptide Aβ 1-40 was studied by adding Cu（II） in the absence and presence of 4th generation poly（propyleneimine） glycodendrimer functionalized with sulfate groups, using dynamic light scattering （DLS）, circular dichroism （CD）, fluorescence, electron paramagnetic resonance （EPR） and molecular modeling （MD）. The glycodendrimer was non-toxic to mHippoE-18 embryonic mouse hippocampal cells, selected as a nerve cell model and decreased the toxicity of peptide aggregates formed after the addition of Cu（II）. The binary systems of Cu（II）-glycodendrimer, Cu（II）-peptide, and glycodendrimer-peptide were first characterized. At the lowest Cu（II）/glycodendrimer molar ratios, Cu（II） was complexed by the internal-dendrimer nitrogen sites. After saturation of these sites, Cu（II） binding with sulfate groups occurred. Stable Cu（II）-peptide complexes formed within 5 min and were responsible for a transition from an α helix to a β-sheet conformation of Aβ 1-40. Glycodendrimer-peptide interactions provoked the stabilization of the a-helix, as demonstrated in the absence of Cu（II） by the Thioflavin T assay, and in the presence of Cu（II） by CD, EPR, and MD. Formation of fibrils is differentially modulated by glycodendrimer and Cu（II） concentrations for a fixed amount of Aβ 1-40. Therefore, this multidisciplinary study facilitated the recognition of optimal experimental conditions that allow the glycodendrimer to avoid the fibril formation induced by Cu（II）.
基金We thank NSFC(Nos.51873050 and 21871069)for financial support.
文摘Inspired by the intricate eukaryotic cell structure,the spontaneously assembling multicompartments capable of spatiotemporally regulated biomacromolecules transportation is still a challenge.Here,a heterogeneous proteinosome-based multicompartment was designed and constructed by combining aqueous two-phase system and Pickering emulsion methods.By loading PEGylated insulin with boronic acid group into the multicompartment and glucose oxidase(GOx)into the innermost microgel domain,a short-or long-term transportation pathway of the loaded insulin was constructed by responding to the concentration of glucose.Moreover,the diminution of dynamic boronic ester bonding,the hindrance of polyethylene oxide micro-chamber,electrostatic interaction and the swelling behavior of hydrogel triggered by GOx/glucose reaction resulted in spatiotemporally controlled multi-pathway transportation mode with the releasing of insulin loaded inside the innermost microgel at high concentration of glucose(10 mg·mL^(-1)).Specially,by incorporating rhodamine B and fluorescein labelled BSA into the multicompartment,the release procedure of the loaded insulin can be monitored by the fluorescence color-change.Overall,a multimode microcompartment is constructed which is then expected to provide a promising platform for further therapeutic protein,gene and drug delivery,as well as towards the design of complicated cell biomimetics.
