Alzheimer’s disease(AD),one of the most common neurodegenerative diseases worldwide,is characterised by the self-assembly of amyloid-β peptides(Aβ)in senile plaques,which are also rich in metal ions such as Cu and ...Alzheimer’s disease(AD),one of the most common neurodegenerative diseases worldwide,is characterised by the self-assembly of amyloid-β peptides(Aβ)in senile plaques,which are also rich in metal ions such as Cu and Zn.Here,we investigated the influence of Zn(Ⅱ)ions on the self-and co-assembly of Aβ_(1-40) and N-terminally truncated Aβ_(4-40) peptides,the two most prevalent Aβ peptides in the brain.The Zn(Ⅱ)coordination site in the soluble model peptide Aβ_(4-16 )was investigated for the first time through pH-dependent X-ray absorption spectroscopy and nuclear magnetic resonance measurements,suggesting the formation of two species around neutral pH,depending on the(de)protonation of the N-terminal amine.The Zn(Ⅱ)affinity was assessed via robust competition experiments,showing that Aβ_(4-16) has a four-fold lower affinity than Aβ_(1-16).The self-assembly of Aβ_(1-40) and Aβ_(4-40),and their co-assembly were monitored in the presence of various Zn(Ⅱ)levels,which revealed an important concentration-dependent modulatory effect of Zn(Ⅱ)ions.In particular,the interplay between Zn(Ⅱ),Aβ_(1-40) and Aβ_(4-40),compared to either binary Zn-Aβ_(x-40) systems,promotes the formation of ill-defined assemblies regarded as more toxic than fibrils.This study provides more biologically relevant insights into the complex interaction between Zn(Ⅱ)ions and the two major forms of Aβ peptides detected in senile plaques,underscoring their significance in the pathophysiology of AD.展开更多
基金the ANR SUPRAMY(ANR-21-CE06-0030)supported by the MITI 80PRIME program of the CNRS to N.V.and C.H.(contract#256994)the European Synchrotron Radiation Facility(ESRF,Grenoble)for the provision of synchrotron radiation facilities under proposal numbers LS-3238 and LS-3308.
文摘Alzheimer’s disease(AD),one of the most common neurodegenerative diseases worldwide,is characterised by the self-assembly of amyloid-β peptides(Aβ)in senile plaques,which are also rich in metal ions such as Cu and Zn.Here,we investigated the influence of Zn(Ⅱ)ions on the self-and co-assembly of Aβ_(1-40) and N-terminally truncated Aβ_(4-40) peptides,the two most prevalent Aβ peptides in the brain.The Zn(Ⅱ)coordination site in the soluble model peptide Aβ_(4-16 )was investigated for the first time through pH-dependent X-ray absorption spectroscopy and nuclear magnetic resonance measurements,suggesting the formation of two species around neutral pH,depending on the(de)protonation of the N-terminal amine.The Zn(Ⅱ)affinity was assessed via robust competition experiments,showing that Aβ_(4-16) has a four-fold lower affinity than Aβ_(1-16).The self-assembly of Aβ_(1-40) and Aβ_(4-40),and their co-assembly were monitored in the presence of various Zn(Ⅱ)levels,which revealed an important concentration-dependent modulatory effect of Zn(Ⅱ)ions.In particular,the interplay between Zn(Ⅱ),Aβ_(1-40) and Aβ_(4-40),compared to either binary Zn-Aβ_(x-40) systems,promotes the formation of ill-defined assemblies regarded as more toxic than fibrils.This study provides more biologically relevant insights into the complex interaction between Zn(Ⅱ)ions and the two major forms of Aβ peptides detected in senile plaques,underscoring their significance in the pathophysiology of AD.
