Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure

Konstantoulea, Katerina; Guerreiro, Patrícia; Ramakers, Meine; Louros, Nikolaos; Aubrey, Liam D.; Houben, Bert; Michiels, Emiel; Vleeschouwer, Matthias De; Lampi, Youlia; Ribeiro, Luís F.; Wit, Joris de; Xue, Wei‐Feng; Schymkowitz, Joost; Rousseau, Frédéric

doi:10.15252/embj.2021108591

Cited by 27 publications

(16 citation statements)

References 96 publications

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“…Met-Aβ was produced in-house as previously described 63 using the human Met-Aβ1–42 expression plasmid, provided by C. Gomes. The C-terminal medin fragment (CT-medin: EVTGIITQGARNFGSVQFVASYK) was synthesized using an Intavis Multipep RSi solid phase peptide synthesis robot.…”

Section: Methodsmentioning

confidence: 99%

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Wagner

Degenhardt

Veit

et al. 2022

Nature

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Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.

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Section: Methodsmentioning

confidence: 99%

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Wagner

Degenhardt

Veit

et al. 2022

Nature

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“…The mechanism by which two different peptides form amyloids is not well understood. However, recent evidence suggests that heterotypic interactions between proteins via aggregation-prone homologous segments may contribute to it [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition

et al. 2022

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Most neurodegenerative diseases such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics.

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“…The in vitro co-aggregation data presented here and in previous studies ( Yan et al, 2007 , 2014 ; Hu et al, 2015 ; Young et al, 2015 ; Ge et al, 2018 ; Bharadwaj et al, 2020 ), emphasize the significance of the cross-amyloid mechanism in establishing the association between AD and T2D. In addition to IAPP and Aβ40 co-aggregation, the co-aggregation of other proteins such as Tau and α-Synuclein ( Giasson, 2003 ), IAPP and α-Synuclein ( Horvath and Wittung-Stafshede, 2016 ), IAPP and Tau-Fragment R3 ( Arya et al, 2019 ), Aβ and α-Synuclein ( Luo et al, 2016 ; Bhasne and Mukhopadhyay, 2018 ; Köppen et al, 2020 ) were reported which can elucidate the cross-talk of other protein misfolding diseases ( Luo et al, 2016 ; Bharadwaj et al, 2017 ; Ren et al, 2019 ; Konstantoulea et al, 2021a ). Given that cross-interaction can result in unique assemblies and cytotoxic hetero-aggregates, it is important to investigate the prevention of such processes which is also a strategy suggested by a review addressing the cross-interaction of Aβ with 10 amyloid-related proteins ( Luo et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Linking Alzheimer’s Disease and Type 2 Diabetes: Characterization and Inhibition of Cytotoxic Aβ and IAPP Hetero-Aggregates

Adem

Shanti

Srivastava

et al. 2022

Front. Mol. Biosci.

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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.

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Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure

Cited by 27 publications

References 96 publications

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition

Linking Alzheimer’s Disease and Type 2 Diabetes: Characterization and Inhibition of Cytotoxic Aβ and IAPP Hetero-Aggregates

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