scholarly journals Evaluation of Amyloid Polypeptide Aggregation Inhibition and Disaggregation Activity of A-Type Procyanidins

2021 ◽  
Vol 14 (11) ◽  
pp. 1118
Author(s):  
Taisei Tanaka ◽  
Vipul V. Betkekar ◽  
Ken Ohmori ◽  
Keisuke Suzuki ◽  
Hideyuki Shigemori
Keyword(s):  
Daily Intake ◽  
Amyloid Β ◽  
Islet Amyloid ◽  
Transmission Electron ◽  
Amyloid Aggregates ◽  
Aggregation Inhibition ◽  
Aggregation And Disaggregation ◽  
Amyloid Polypeptides ◽  
The Brain

The number of people worldwide suffering from Alzheimer’s disease (AD) and type 2 diabetes (T2D) is on the rise. Amyloid polypeptides are thought to be associated with the onset of both diseases. Amyloid-β (Aβ) that aggregates in the brain and human islet amyloid polypeptide (hIAPP) that aggregates in the pancreas are considered cytotoxic and the cause of the development of AD and T2D, respectively. Thus, inhibiting amyloid polypeptide aggregation and disaggregation existing amyloid aggregates are promising approaches in the therapy and prevention against both diseases. Therefore, in this research, we evaluated the Aβ/hIAPP anti-aggregation and disaggregation activities of A-type procyanidins 1–7 and their substructures 8 and 9, by conducting structure–activity relationship studies and identified the active site. The thioflavin-T (Th-T) assay, which quantifies the degree of aggregation of amyloid polypeptides based on fluorescence intensity, and transmission electron microscopy (TEM), employed to directly observe amyloid polypeptides, were used to evaluate the activity. The results showed that catechol-containing compounds 1–6 exhibited Aβ/hIAPP anti-aggregation and disaggregation activities, while compound 7, without catechol, showed no activity. This suggests that the presence of catechol is important for both activities. Daily intake of foods containing A-type procyanidins may be effective in the prevention and treatment of both diseases.

scholarly journals Inhibitory Activity on Amyloid Aggregation of Rosmarinic Acid and Its Substructures From Isodon japonicus

2019 ◽  
Vol 14 (5) ◽  
pp. 1934578X1984303 ◽  
Author(s):  
Jiayi Sun ◽  
Gandan Jiang ◽  
Hideyuki Shigemori
Keyword(s):  
Antioxidant Activity ◽  
Inhibitory Activity ◽  
Rosmarinic Acid ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Islet Amyloid ◽  
Promising Strategy ◽  
Transmission Electron ◽  
The Relationship

Nowadays, the incidence of Alzheimer’s disease (AD) and type 2 diabetes (T2D) is increasing at an alarming rate. More and more studies have been investigating the relationship between these two diseases and are trying to find an effective treatment. According to amyloid hypothesis, it is very necessary to find phenolic compounds with catechol moieties, which would inhibit the aggregation of amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP), while also exhibiting antioxidant activity and protective effect. We isolated rosmarinic acid (RA) from the plant Isodon japonicus (Burm.f.) H. Hara. Thioflavin T assay and transmission electron microscopy observation were carried out to evaluate the inhibitory effect of RA, caffeic acid, and 3,4-dihydroxyphenyllactic acid, which are the substructures of RA, on both Aβ and hIAPP fibrillization. 2,2-Diphenyl-1-picrylhydrazyl assay was applied to test the antioxidant activity. RA showed inhibitory effect on both peptides and strong antioxidant activity. These results suggest that the existence of catechol units plays an important role on the inhibitory activity. Therefore, RA will be a promising strategy to prevent AD and T2D.

scholarly journals Human Islet Amyloid Polypeptide Fibril Binding to Catalase: A Transmission Electron Microscopy and Microplate Study

2010 ◽  
Vol 10 ◽  
pp. 879-893 ◽  
Author(s):  
Nathaniel G. N. Milton ◽  
J. Robin Harris
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Transmission Electron

The diabetes-associated human islet amyloid polypeptide (IAPP) is a 37-amino-acid peptide that forms fibrilsin vitroandin vivo. Human IAPP fibrils are toxic in a similar manner to Alzheimer's amyloid-β (Aβ) and prion protein (PrP) fibrils. Previous studies have shown that catalase binds to Aβ fibrils and appears to recognize a region containing the Gly-Ala-Ile-Ile sequence that is similar to the Gly-Ala-Ile-Leu sequence found in human IAPP residues 24-27. This study presents a transmission electron microscopy (TEM)—based analysis of fibril formation and the binding of human erythrocyte catalase to IAPP fibrils. The results show that human IAPP 1-37, 8-37, and 20-29 peptides form fibrils with diverse and polymorphic structures. All three forms of IAPP bound catalase, and complexes of IAPP 1-37 or 8-37 with catalase were identified by immunoassay. The binding of biotinylated IAPP to catalase was high affinity with a KDof 0.77nM, and could be inhibited by either human or rat IAPP 1-37 and 8-37 forms. Fibrils formed by the PrP 118-135 peptide with a Gly-Ala-Val-Val sequence also bound catalase. These results suggest that catalase recognizes a Gly-Ala-Ile-Leu—like sequence in amyloid fibril-forming peptides. For IAPP 1-37 and 8-37, the catalase binding was primarily directed towards fibrillar rather than ribbon-like structures, suggesting differences in the accessibility of the human IAPP 24-27 Gly-Ala-Ile-Leu region. This suggests that catalase may be able to discriminate between different structural forms of IAPP fibrils. The ability of catalase to bind IAPP, Aβ, and PrP fibrils demonstrates the presence of similar accessible structural motifs that may be targets for antiamyloid therapeutic development.

scholarly journals Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Diana C Rodriguez Camargo ◽  
Kyle J Korshavn ◽  
Alexander Jussupow ◽  
Kolio Raltchev ◽  
David Goricanec ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Md Simulations ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Induce Cell Death

Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

scholarly journals Destruction of Amyloid Fibrils of Keratoepithelin Peptides by Laser Irradiation Coupled with Amyloid-specific Thioflavin T

2011 ◽  
Vol 286 (12) ◽  
pp. 10856-10863 ◽  
Author(s):  
Daisaku Ozawa ◽  
Yuichi Kaji ◽  
Hisashi Yagi ◽  
Kazumasa Sakurai ◽  
Toru Kawakami ◽  
...  
Keyword(s):  
Laser Irradiation ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Corneal Dystrophy ◽  
Thioflavin T ◽  
Corneal Dystrophies ◽  
Amyloid Aggregates ◽  
Granular Corneal Dystrophy

Mutations in keratoepithelin are associated with blinding ocular diseases, including lattice corneal dystrophy type 1 and granular corneal dystrophy type 2. These diseases are characterized by deposits of amyloid fibrils and/or granular non-amyloid aggregates in the cornea. Removing the deposits in the cornea is important for treatment. Previously, we reported the destruction of amyloid fibrils of β2-microglobulin K3 fragments and amyloid β by laser irradiation coupled with the binding of an amyloid-specific thioflavin T. Here, we studied the effects of this combination on the amyloid fibrils of two 22-residue fragments of keratoepithelin. The direct observation of individual amyloid fibrils was performed in real time using total internal reflection fluorescence microscopy. Both types of amyloid fibrils were broken up by the laser irradiation, dependent on the laser power. The results suggest the laser-induced destruction of amyloid fibrils to be a useful strategy for the treatment of these corneal dystrophies.

Glycated Insulin Exacerbates the Cytotoxicity of Human Islet Amyloid Polypeptides: a Vicious Cycle in Type 2 Diabetes

2019 ◽  
Vol 14 (3) ◽  
pp. 486-496 ◽  
Author(s):  
Liang Ma ◽  
Chen Yang ◽  
Lianqi Huang ◽  
Yuchen Chen ◽  
Yang Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Human Islet ◽  
Vicious Cycle ◽  
Islet Amyloid ◽  
Amyloid Polypeptides

Amyloid‐β and islet amyloid pathologies link Alzheimer’s disease and type 2 diabetes in a transgenic model

2017 ◽  
Vol 31 (12) ◽  
pp. 5409-5418 ◽  
Author(s):  
Nadeeja Wijesekara ◽  
Rosemary Ahrens ◽  
Miheer Sabale ◽  
Ling Wu ◽  
Kathy Ha ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Islet Amyloid ◽  
Transgenic Model

scholarly journals Amyloid-Mediated Mechanisms of Membrane Disruption

Biophysica ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 137-156
Author(s):  
Michele F. M. Sciacca ◽  
Carmelo La Rosa ◽  
Danilo Milardi
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Conformational Transition ◽  
Prion Diseases ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Amyloid Aggregates ◽  
Abnormal Accumulation

Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies.

scholarly journals Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus

2021 ◽  
Vol 15 ◽  
Author(s):  
A. Young Sim ◽  
Sumit Barua ◽  
Jong Youl Kim ◽  
Yong-ho Lee ◽  
Jong Eun Lee
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Inflammatory Responses ◽  
Memory Loss ◽  
Amyloid Β ◽  
Sglt2 Inhibitors ◽  
Chronic Hyperglycemia ◽  
The Brain

Alzheimer’s disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.

scholarly journals Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease

2020 ◽  
Vol 21 (9) ◽  
pp. 3165 ◽  
Author(s):  
Thuy Trang Nguyen ◽  
Qui Thanh Hoai Ta ◽  
Thi Kim Oanh Nguyen ◽  
Thi Thuy Dung Nguyen ◽  
Vo Van Giau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Type 3 Diabetes ◽  
Slowing Down ◽  
Type 3 ◽  
The Relationship ◽  
The Brain ◽  
Protein Toxicity

The exact connection between Alzheimer’s disease (AD) and type 2 diabetes is still in debate. However, poorly controlled blood sugar may increase the risk of developing Alzheimer’s. This relationship is so strong that some have called Alzheimer’s “diabetes of the brain” or “type 3 diabetes (T3D)”. Given more recent studies continue to indicate evidence linking T3D with AD, this review aims to demonstrate the relationship between T3D and AD based on the fact that both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ are attributed to impaired insulin signaling, and that insulin resistance mediates the dysregulation of bioenergetics and progress to AD. Furthermore, insulin-related therapeutic strategies are suggested to succeed in the development of therapies for AD by slowing down their progressive nature or even halting their future complications.

Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations

2008 ◽  
Vol 33 (3) ◽  
pp. 355-360 ◽  
Author(s):  
Karen M. Eny ◽  
Thomas M. S. Wolever ◽  
Bénédicte Fontaine-Bisson ◽  
Ahmed El-Sohemy
Keyword(s):  
Genetic Variation ◽  
Food Intake ◽  
Glucose Transporter ◽  
Glucose Sensor ◽  
Daily Intake ◽  
Glucose Sensing ◽  
Younger Adults ◽  
Food Records ◽  
The Brain

Glucose sensing in the brain has been proposed to be involved in regulating food intake, but the mechanism is not known. Glucose transporter type 2 (GLUT2)-null mice fail to control their food intake in response to glucose, suggesting a potential role for this transporter as a glucose sensor in the brain. Here we show that individuals with a genetic variation in GLUT2 (Thr110Ile) have a higher daily intake of sugars in two distinct populations. In the first population, compared with individuals with the Thr/Thr genotype, carriers of the Ile allele had a significantly higher intake of sugars as assessed from 3-day food records administered on two separate visits ( visit 1: 112 ± 9 vs. 86 ± 4 g/day, P = 0.01; visit 2: 111 ± 8 vs. 82 ± 4 g/day, P = 0.003), demonstrating within-population reproducibility. In a second population, carriers of the Ile allele also reported consuming a significantly greater intake of sugars (131 ± 5 vs. 115 ± 3 g/day, P = 0.007) over a 1-mo period as measured from a food frequency questionnaire. GLUT2 genotypes were not associated with fat, protein, or alcohol intake in either population. These observations were consistent across older and younger adults as well as among subjects with early Type 2 diabetes and healthy individuals. Taken together, our findings show that a genetic variation in GLUT2 is associated with habitual consumption of sugars, suggesting an underlying glucose-sensing mechanism that regulates food intake.

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