Studies on the cross-interaction between hIAPP and Aβ 25-35 and the aggregation process in binary mixture by electrospray ionization-ion mobility-mass spectrometry.
JOURNAL OF MASS SPECTROMETRY(2020)
摘要
A wealth of epidemiological evidence indicates a strong link between type 2 diabetes (T2D) and Alzheimer's disease (AD). The fiber deposition with cross-beta-sheet structure formed by self-aggregation and misfolding of amyloidogenic peptides is a common hallmark of both diseases. For the patients with T2D, the fibrils are mainly found in the islets of Langerhans that results from the accumulation of human islet amyloid polypeptide (hIAPP). The major component of aggregates located in the brain of AD patients is amyloid-beta (A beta). Many biophysical and physiological properties are shared by hIAPP and A beta, and both peptides show similar cytotoxic mechanisms. Therefore, it is meaningful to investigate the possible cross-interactions of hIAPP and A beta in both diseases. In this article, the segment 25-35 of A beta was selected because A beta(25-35)was a core region in the process of amyloid formation and showed similar aggregation tendency and toxicity with full-length A beta. The electrospray ionization-ion mobility-mass spectrometry analysis and thioflavin T fluorescence kinetic analysis combined with transmission electron microscopy were used to explore the effects of the coexistence of A beta(25-35)and hIAPP on the self-aggregation of both peptides and whether there was co-assembly in fibrilla tion. The results indicated that the aggregation of hIAPP and A beta(25-35) had two nucleation stages in the binary mixtures. hIAPP and A beta(25-35) had a high binding affinity and a series of hetero-oligomers formed in the mixtures of hIAPP and A beta(25-35) in the early stage. The cross-reaction between hIAPP monomers and A beta(25-35) monomers as well as a little of oligomers during primary nucleation stage could accelerate the aggregation of A beta(25-35). However, owing to the obvious difference in aggregation ability between hIAPP and A beta(25-35), this cross-interaction had no significant impact on the self-assembly of hIAPP. Our study may offer a better understanding for exploring the molecular mechanism of the association between AD and T2D observed in clinical and epidemiological studies and developing therapeutic strategies against amyloid diseases.
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关键词
aggregation,Alzheimer's disease,amyloid-beta(25-35),human islet amyloid polypeptide,interaction,ion mobility-mass spectrometry,type 2 diabetes
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