TY - JOUR
T1 - Linking Alzheimer’s Disease and Type 2 Diabetes
T2 - Characterization and Inhibition of Cytotoxic Aβ and IAPP Hetero-Aggregates
AU - Al Adem, Kenana
AU - Shanti, Aya
AU - Srivastava, Amit
AU - Homouz, Dirar
AU - Thomas, Sneha Ann
AU - Khair, Mostafa
AU - Stefanini, Cesare
AU - Chan, Vincent
AU - Kim, Tae Yeon
AU - Lee, Sungmun
N1 - Funding Information:
KA conceived the study; designed the experiments; acquired, presented, analysed and discussed data (all figures); wrote the manuscript. AyS designed experiments; discussed data; edited the manuscript. AmS and DH performed and analyzed molecular dynamics simulations. ST and MK. performed and analyzed CD experiments. TK, CS, and VC conceived the study; edited manuscript and provided financial support. SL conceived the study, designed the experiments, analyzed and discussed data (all figures), edited the manuscript and provided financial support. All authors edited the manuscript and approved the final version.
Publisher Copyright:
Copyright © 2022 Al Adem, Shanti, Srivastava, Homouz, Thomas, Khair, Stefanini, Chan, Kim and Lee.
PY - 2022/3/17
Y1 - 2022/3/17
N2 - The cytotoxic self-aggregation of β-amyloid (Aβ) peptide and islet amyloid polypeptide (IAPP) is implicated in the pathogenesis of Alzheimer’s disease (AD) and Type 2 diabetes (T2D), respectively. Increasing evidence, particularly the co-deposition of Aβ and IAPP in both brain and pancreatic tissues, suggests that Aβ and IAPP cross-interaction may be responsible for a pathological link between AD and T2D. Here, we examined the nature of IAPP-Aβ40 co-aggregation and its inhibition by small molecules. In specific, we characterized the kinetic profiles, morphologies, secondary structures and toxicities of IAPP-Aβ40 hetero-assemblies and compared them to those formed by their homo-assemblies. We demonstrated that monomeric IAPP and Aβ40 form stable hetero-dimers and hetero-assemblies that further aggregate into β-sheet-rich hetero-aggregates that are toxic (cell viability <50%) to both PC-12 cells, a neuronal cell model, and RIN-m5F cells, a pancreatic cell model for β-cells. We then selected polyphenolic candidates to inhibit IAPP or Aβ40 self-aggregation and examined the inhibitory effect of the most potent candidate on IAPP-Aβ40 co-aggregation. We demonstrated that epigallocatechin gallate (EGCG) form inter-molecular hydrogen bonds with each of IAPP and Aβ40. We also showed that EGCG reduced hetero-aggregate formation and resulted in lower β-sheets content and higher unordered structures in IAPP-Aβ40-EGCG samples. Importantly, we showed that EGCG is highly effective in reducing the toxicity of IAPP-Aβ40 hetero-aggregates on both cell models, specifically at concentrations that are equivalent to or are 2.5-fold higher than the mixed peptide concentrations. To the best of our knowledge, this is the first study to report the inhibition of IAPP-Aβ40 co-aggregation by small molecules. We conclude that EGCG is a promising candidate to prevent co-aggregation and cytotoxicity of IAPP-Aβ40, which in turn, contribute to the pathological link between AD and T2D.
AB - The cytotoxic self-aggregation of β-amyloid (Aβ) peptide and islet amyloid polypeptide (IAPP) is implicated in the pathogenesis of Alzheimer’s disease (AD) and Type 2 diabetes (T2D), respectively. Increasing evidence, particularly the co-deposition of Aβ and IAPP in both brain and pancreatic tissues, suggests that Aβ and IAPP cross-interaction may be responsible for a pathological link between AD and T2D. Here, we examined the nature of IAPP-Aβ40 co-aggregation and its inhibition by small molecules. In specific, we characterized the kinetic profiles, morphologies, secondary structures and toxicities of IAPP-Aβ40 hetero-assemblies and compared them to those formed by their homo-assemblies. We demonstrated that monomeric IAPP and Aβ40 form stable hetero-dimers and hetero-assemblies that further aggregate into β-sheet-rich hetero-aggregates that are toxic (cell viability <50%) to both PC-12 cells, a neuronal cell model, and RIN-m5F cells, a pancreatic cell model for β-cells. We then selected polyphenolic candidates to inhibit IAPP or Aβ40 self-aggregation and examined the inhibitory effect of the most potent candidate on IAPP-Aβ40 co-aggregation. We demonstrated that epigallocatechin gallate (EGCG) form inter-molecular hydrogen bonds with each of IAPP and Aβ40. We also showed that EGCG reduced hetero-aggregate formation and resulted in lower β-sheets content and higher unordered structures in IAPP-Aβ40-EGCG samples. Importantly, we showed that EGCG is highly effective in reducing the toxicity of IAPP-Aβ40 hetero-aggregates on both cell models, specifically at concentrations that are equivalent to or are 2.5-fold higher than the mixed peptide concentrations. To the best of our knowledge, this is the first study to report the inhibition of IAPP-Aβ40 co-aggregation by small molecules. We conclude that EGCG is a promising candidate to prevent co-aggregation and cytotoxicity of IAPP-Aβ40, which in turn, contribute to the pathological link between AD and T2D.
KW - cellular toxicity
KW - co-aggregation
KW - co-aggregation inhibition
KW - cross-interaction
KW - cross-seeding
KW - epigallocatechin gallate
KW - islet amyloid polypeptide
KW - β-amyloid
UR - http://www.scopus.com/inward/record.url?scp=85127904582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127904582&partnerID=8YFLogxK
U2 - 10.3389/fmolb.2022.842582
DO - 10.3389/fmolb.2022.842582
M3 - Article
AN - SCOPUS:85127904582
SN - 2296-889X
VL - 9
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 842582
ER -