Evidence suggests that increased level/aggregation of beta-amyloid(Aβ)peptides initiate neurodegeneration and subsequent development of Alzheimer’s disease(AD).At present,there is no effective treatment for AD.In th...Evidence suggests that increased level/aggregation of beta-amyloid(Aβ)peptides initiate neurodegeneration and subsequent development of Alzheimer’s disease(AD).At present,there is no effective treatment for AD.In this study,we reported the effects of gold nanoparticles surface-functionalized with a plant-based amino acid mimosine(Mimo-AuNPs),which is found to cross the blood-brain barrier,on the Aβfibrillization process and toxicity.Thioflavin T kinetic assays,fluorescence imaging and electron microscopy data showed that Mimo-AuNPs were able to suppress the spontaneous and seed-induced A_(1-42) aggregation.Spectroscopic studies,molecular docking and biochemical analyses further revealed that Mimo-AuNPs stabilize A_(1-42) to remain in its monomeric state by interacting with the hydrophobic domain of A_(1-42)(i.e.,Lys16 to Ala21)there by preventing a conformational shift towards theβ-sheet structure.Additionally,Mimo-AuNPs were found to trigger the disassembly of matured A_(1-42) fibers and increased neuronal viability by reducing phosphorylation of tau protein and the production of oxyradicals.Collectively,these results reveal that the surface-functionalization of gold nanoparticles with mimosine can attenuate Aβfibrillization and neuronal toxicity.Thus,we propose Mimo-AuNPs may be used as a potential treatment strategy towards AD-related pathologies.展开更多
Alzheimer’s disease (AD) is believed to be triggered by increased levels/aggregation of β-amyloid (Aβ) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeu...Alzheimer’s disease (AD) is believed to be triggered by increased levels/aggregation of β-amyloid (Aβ) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeutic potential of FDA-approved native poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles on Aβ aggregation and in cellular/ animal models of AD. Our results showed that native PLGA can not only suppress the spontaneous aggregation but can also trigger disassembly of preformed Aβ aggregates. Spectroscopic studies, molecular dynamics simu-lations and biochemical analyses revealed that PLGA, by interacting with the hydrophobic domain of Aβ1-42, prevents a conformational shift towards the β-sheet structure, thus precluding the formation and/or triggering disassembly of Aβ aggregates. PLGA-treated Aβ samples can enhance neuronal viability by reducing phosphor-ylation of tau protein and its associated signaling mechanisms. Administration of PLGA can interact with Aβ aggregates and attenuate memory deficits as well as Aβ levels/deposits in the 5xFAD mouse model of AD. PLGA can also protect iPSC-derived neurons from AD patients against Aβ toxicity by decreasing tau phosphorylation. These findings provide unambiguous evidence that native PLGA, by targeting different facets of the Aβ axis, can have beneficial effects in mouse neurons/animal models as well as on iPSC-derived AD neurons - thus signifying its unique therapeutic potential in the treatment of AD pathology.展开更多
基金This work was supported by grants from APRI-ASANT and CIHR(MOP-84480)SK and from APRI(APRI 201600028)HW.SynAD,University of Alberta provided a part of the postdoctoral fellowships for BGA,QW and KG.
文摘Evidence suggests that increased level/aggregation of beta-amyloid(Aβ)peptides initiate neurodegeneration and subsequent development of Alzheimer’s disease(AD).At present,there is no effective treatment for AD.In this study,we reported the effects of gold nanoparticles surface-functionalized with a plant-based amino acid mimosine(Mimo-AuNPs),which is found to cross the blood-brain barrier,on the Aβfibrillization process and toxicity.Thioflavin T kinetic assays,fluorescence imaging and electron microscopy data showed that Mimo-AuNPs were able to suppress the spontaneous and seed-induced A_(1-42) aggregation.Spectroscopic studies,molecular docking and biochemical analyses further revealed that Mimo-AuNPs stabilize A_(1-42) to remain in its monomeric state by interacting with the hydrophobic domain of A_(1-42)(i.e.,Lys16 to Ala21)there by preventing a conformational shift towards theβ-sheet structure.Additionally,Mimo-AuNPs were found to trigger the disassembly of matured A_(1-42) fibers and increased neuronal viability by reducing phosphorylation of tau protein and the production of oxyradicals.Collectively,these results reveal that the surface-functionalization of gold nanoparticles with mimosine can attenuate Aβfibrillization and neuronal toxicity.Thus,we propose Mimo-AuNPs may be used as a potential treatment strategy towards AD-related pathologies.
文摘Alzheimer’s disease (AD) is believed to be triggered by increased levels/aggregation of β-amyloid (Aβ) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeutic potential of FDA-approved native poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles on Aβ aggregation and in cellular/ animal models of AD. Our results showed that native PLGA can not only suppress the spontaneous aggregation but can also trigger disassembly of preformed Aβ aggregates. Spectroscopic studies, molecular dynamics simu-lations and biochemical analyses revealed that PLGA, by interacting with the hydrophobic domain of Aβ1-42, prevents a conformational shift towards the β-sheet structure, thus precluding the formation and/or triggering disassembly of Aβ aggregates. PLGA-treated Aβ samples can enhance neuronal viability by reducing phosphor-ylation of tau protein and its associated signaling mechanisms. Administration of PLGA can interact with Aβ aggregates and attenuate memory deficits as well as Aβ levels/deposits in the 5xFAD mouse model of AD. PLGA can also protect iPSC-derived neurons from AD patients against Aβ toxicity by decreasing tau phosphorylation. These findings provide unambiguous evidence that native PLGA, by targeting different facets of the Aβ axis, can have beneficial effects in mouse neurons/animal models as well as on iPSC-derived AD neurons - thus signifying its unique therapeutic potential in the treatment of AD pathology.
