Amylin Oligomers Research Articles

Exploring membrane damage mechanisms of heterogeneous tau and amylin oligomers in Alzheimer's using MD simulations

Exploring membrane damage mechanisms of heterogeneous tau and amylin oligomers in Alzheimer's using MD simulations

Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s

The disruption of cell membranes by tau and amylin oligomers is linked to amyloid diseases such as Alzheimer’s and diabetes, respectively. The recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-oligomers that are structurally different from homo-oligomers. However, the molecular interactions of these hetero-oligomers with the neuronal membranes remain unclear. Using MD simulations, we have investigated the binding behaviors, membrane disruption, and protein folding of hetero-oligomers on a raft membrane containing phase-separated lipid nanodomains like those found in neurons. We discovered that the hetero-oligomers bind to the liquid-order and liquid-disorder phase boundaries of the raft membrane. The major lipid-binding sites of these interactions include the L16 and I26 residues of amylin and the N-terminal of tau. Strong disruptions of the raft domain size by the hetero-tetramer were detected. Furthermore, the hetero-dimer disrupted the saturated phospholipid orientational order to a greater extent than the individual tau or amylin monomer. In addition, the constituent tau more strongly promoted the alpha-helix to the beta-sheet transition of the constituent amylin within the hetero-dimer when compared with the amylin monomer alone. Our results provide new molecular insights into understanding the neurotoxicity of the hetero-oligomers associated with the cross-talk between amyloid diseases.

Nanoparticles and Nanocolloidal Carbon: Will They Be the Next Antidiabetic Class That Targets Fibrillation and Aggregation of Human Islet Amyloid Polypeptide in Type 2 Diabetes?

Nanotechnology is revolutionizing human medicine. Nanoparticles (NPs) are currently used for treating various cancers, for developing vaccines, and for imaging, and other promises offered by NPs might come true soon. Due to the interplay between NPs and proteins, there is more and more evidence supporting the role of NPs for treating amyloid-based diseases. NPs can induce some conformational changes of the adsorbed protein molecules via various molecular interactions, leading to inhibition of aggregation and fibrillation of several and different amyloid proteins. Though an in depth understanding of such interactions between NPs and amyloid structures is still lacking, the inhibition of protein aggregation by NPs represents a new generation of innovative and effective medicines to combat metabolic diseases such as type 2 diabetes (T2D). Here, we lay out advances made in the field of T2D notably for optimizing protein aggregation inhibition strategies. This Account covers discussions about the current understanding of β-cells, the insulin producing cells within the pancreas, under diabetic conditions, notably increased glucose and fatty acid levels, and the implication of these conditions on the formation of human islet amyloid polypeptide (hIAPP) amylin oligomers and aggregates. Owing to the great potential of carbon nanostructures to interfere with protein aggregation, an important part of this Account will be devoted to the state of the art of therapeutic options in the form of emerging nanomaterials-based amyloidosis inhibitors. Our group has recently made some substantial progress in this regard by investigating the impact of glucose and fatty acid concentrations on hIAPP aggregation and β-cell toxicity. Furthermore, the great potential of carbon nanocolloids in reversing hIAPP aggregation under diabetic conditions will be highlighted as the approach has been validated on β-cell cultures from rats. We hope that this Account will evoke new ideas and concepts in this regard. We give some lead references below on pancreatic β-cell aspects and carbon quantum dots for managing diabetics and nanomedicine related aspects, a topic of interest in our laboratory.

IDF21-0191 Plumbagin and Plumbagin amino acid ester conjugates inhibit amylin priori and post-priori

Background: Amylin/IAPP is a 37 amino acid neuropeptide hormone. Amylin forms oligomers in diabetic conditions when loss of insulin secretion occurs. These amylin oligomers are implicated in development and poor prognosis of type 2 DM. Amylin oligomers are shown to induce diabetes-associated secondary complications. In human amylin over expressed rat, and human studies, it is shown that amylin oligomers lead to diabetes-associated cardiomyopathy, neuropathy and nephropathy. There is an immediate requirement to develop novel inhibitor for amylin oligomers towards preventing these complications.

Amylin oligomers stabilize membrane rafts

Amylin aggregation is associated with type 2 diabetes. The interaction of intermediate small oligomers with the membrane is a crucial step in their toxicity and is dependent on the membrane order. But the exact role of membrane phases in amylin toxicity is not known. Therefore, understanding the interaction of the toxic small oligomers of amylin with the coexisting membrane phases and elucidating the role of phase boundaries are important. Here, we have used biphasic supported lipid bilayers and studied membrane phase-dependent interactions of amylin oligomers using a home-built combined atomic force (AFM)-fluorescence confocal -fluorescence lifetime imaging set-up.

Amylin: new insight into pathogenesis, diagnosis, and prognosis of non-insulin-dependent diabetes-mellitus-related cardiomyopathy

Abstract Co-secretion with insulin, highly amyloidogenic human amylin is considered to contribute to the initiation and progression of diabetic heart complications, despite other situations such as hypertension and atherosclerosis. In response to insulin resistance, hyperinsulinemia, and consequently hyperamylinemia, is common in prediabetic patients, where highly concentrated amylin is prone to form amylin oligomers, which further assemble into fibrils and amyloids with high β-sheet content. The infusion and deposition of oligomeric amylin in myocytes cause a series of consequences, including cytosolic Ca2+ dysregulation, calmodulin activation, myocyte hypertrophy, and ventricular stiffness, eventually leading to heart failure. In this review, we present the latest reports of amylin-related heart complications, provide new insights, and state the underlying pathogenesis, diagnosis, possible treatment, and prevention of diabetic cardiomyopathy.

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review.

Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.

Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress.

Human amylin or islet amyloid polypeptide (hIAPP) is synthesized in the pancreatic β-cells and has been shown to contribute to the pathogenesis of type 2 diabetes (T2D) in vitro and in vivo. This study compared amylin oligomerization/expression and signal transduction under endoplasmic reticulum (ER) stress and oxidative stress. pCMV-hIAPP-overexpressing INS-1E cells presented different patterns of amylin oligomerization/expression under ER stress and oxidative stress. Amylin oligomerization/expression under ER stress showed three amylin oligomers of less than 15 kDa size in pCMV-hIAPP-overexpressing cells, while one band was detected under oxidative stress. Under ER stress conditions, HIF1α, p-ERK, CHOP, Cu/Zn-SOD, and Bax were significantly increased in pCMV-hIAPP-overexpressing cells compared to the pCMV-Entry-expressing cells (control), whereas p-Akt, p-mTOR, Mn-SOD, catalase, and Bcl-2 were significantly decreased. Under oxidative stress conditions, HIF1α, p-ERK, CHOP, Mn-SOD, catalase, and Bcl-2 were significantly reduced in pCMV-hIAPP-overexpressing cells compared to the control, whereas p-mTOR, Cu/Zn-SOD, and Bax were significantly increased. In mitochondrial oxidative phosphorylation (OXPHOS), the mitochondrial complex I and complex IV were significantly decreased under ER stress conditions and significantly increased under oxidative stress conditions in pCMV-hIAPP-overexpressing cells compared to the control. The present study results demonstrate that amylin undergoes oligomerization under ER stress in pCMV-hIAPP-overexpressing cells. In addition, human amylin overexpression under ER stress in the pancreatic β cells may enhance amylin protein aggregation, resulting in β-cell dysfunction.

Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes.

Protein aggregation is associated with a large number of human protein-misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid (RA) as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200-300 nM). Structure-function relationship analysis of RA showed the additive effects of the two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin but rather lead to nontoxic, remodeled protein aggregates. RA has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of RA treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein-misfolding diseases.

Role and Cytotoxicity of Amylin and Protection of Pancreatic Islet β-Cells from Amylin Cytotoxicity.

Amylin, (or islet amyloid polypeptide; IAPP), a 37-amino acid peptide hormone, is released in response to nutrients, including glucose, lipids or amino acids. Amylin is co-stored and co-secreted with insulin by pancreatic islet β-cells. Amylin inhibits food intake, delays gastric emptying, and decreases blood glucose levels, leading to the reduction of body weight. Therefore, amylin as well as insulin play important roles in controlling the level of blood glucose. However, human amylin aggregates and human amylin oligomers cause membrane disruption, endoplasmic reticulum (ER) stress and mitochondrial damage. Since cytotoxicity of human amylin oligomers to pancreatic islet β-cells can lead to diabetes, the protection of pancreatic islet β cells from cytotoxic amylin is crucial. Human amylin oligomers also inhibit autophagy, although autophagy can function to remove amylin aggregates and damaged organelles. Small molecules, including β-sheet breaker peptides, chemical chaperones, and foldamers, inhibit and disaggregate amyloid formed by human amylin, suggesting the possible use of these small molecules in the treatment of diabetes. In this review, we summarize recent findings regarding the role and cytotoxicity of amylin and the protection of pancreatic islet β-cells from cytotoxicity of amylin.

Single-molecule photobleaching: Instrumentation and applications

Single-molecule photobleaching (smPB) technique is a powerful tool for characterizing molecular assemblies. It can provide a direct measure of the number of monomers constituting a given oligomeric particle and generate the oligomer size distribution in a specimen. A major current application of this technique is in understanding protein aggregation, which is linked to many incurable diseases. Quantitative measurement of the size distribution of an aggregating protein in a physiological solution remains a difficult task, since techniques such as dynamic light scattering or fluorescence correlation spectroscopy (FCS) can provide an average size, but cannot accurately resolve the underlying size distribution. Here we describe the smPB method as implemented on a home-built total internal reflection fluorescence microscope (TIRF). We first describe the construction of a TIRF microscope, and then demonstrate the power of smPB by characterizing a solution of Amylin (hIAPP) oligomers, a 37-residue peptide whose aggregation is associated with Type II diabetes. We compare our results with FCS data obtained from the same specimen, and discuss the advantages and disadvantages of the two techniques.

Structural Insights to Toxic Amylin Oligomers from 2D IR Spectroscopy

Type II Diabetes is classified as an amyloid disease due to the characteristic aggregation of amylin into fiber-like structures. Amylin is a 37 residue peptide that is co-secreted with insulin and is responsible for helping control blood glucose levels. Amylin aggregation is linked to beta-cell death, as it is found aggregated postmortem in patients, but exact nature of its toxicity is unknown. The FGAIL region of the peptide was predicted to be the most amyloidogenic portion of the sequence, but it was not found to be in the beta-sheet region of the final fiber structure as predicted by decades of previous work. Using 2D IR spectroscopy, our group has identified an oligomeric species in the aggregation pathway that contains a beta-sheet in the FGAIL region. By isotope labeling amino acids, we monitor the structure of individual residue throughout the aggregation. The effect of temperature and salt have been investigated on the oligomeric assembly mechanism and stability of the intermediate, as has peptide concentration, which alters the free energy. Toxicity on INS-1 cells is consistent with this intermediate being the cytotoxic species. Our observations tie together disparate observations made over many years and provide a unifying description for the aggregation mechanism of amylin.

Computational modeling of amylin-induced calcium dysregulation in rat ventricular cardiomyocytes

Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca2+. These findings motivate our core hypothesis that non-selective inward Ca2+ conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca2+ load, which thereby magnifies intracellular Ca2+ transients. Questions remain however regarding the mechanism of amylin-induced Ca2+ dysregulation, including whether enhanced SL Ca2+ influx is sufficient to elevate cytosolic Ca2+ load [6], and if so, how might amplified Ca2+ transients perturb Ca2+-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca2+ signaling to reflect experimentally-measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca2+ transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca2+ loading of the SR and that greater fractional release may contribute to the Ca2+-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca2+ in the SR and dyadic space collectively drive greater fractional SR Ca2+ release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca2+ transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca2+ dysregulation in pre-diabetes.

Structural and thermodynamical properties of early human amylin oligomers using replica exchange molecular dynamics: mutation effect of three key residues F15, H18 and F23.

Human islet amyloid polypeptide (hIAPP) is a 37-residue polypeptide, considered to be the main component of the pancreatic islet amyloid associated with type 2 diabetes and is one of the most amyloidogenic polypeptides known. Although the structure of hIAPP fibrils has already been obtained, structures of early oligomers and the mechanism of β-sheet formation remain poorly understood. Herein, we characterize the atomic structure and the thermodynamics of the 14-37 residue fragment of hIAPP wild-type and mutated dimers and trimers. More precisely, three key residues, F15, H18 and F23, thought to affect the aggregation process, are the focus of this numerical study using replica exchange molecular dynamics coupled with the OPEP coarse-grained protein force field. Our simulations show that the oligomerization process takes place through the formation of anti-parallel β-sheets most probably between C-terminal regions. Two main characteristics are associated with the onset of the fibrillation process. First, the sequence matching between the central (20-29) and C-terminal (30-37) regions, at intra and inter-molecular levels, helps in stabilizing the secondary structure and facilitates intermolecular interactions. Second, hydrophobic residues I26 and L27 are likely to promote the capture of further oligomeric structures and thus facilitate fibril elongation. Histidine mutation should have a more pronounced effect in the N-terminal region while phenylalanine mutations do not seem to prevent amyloid formation since central/C-terminal interactions are conserved through other contacts.

Molecular Mechanisms of the Bindings between Non-Amyloid β Component Oligomers and Amylin Oligomers.

It has been suggested that the connection between amyloidogenic diseases is related to the interactions between aggregates of amyloids, which are related to type 2 diabetes and Parkinson's disease. Herein, we illustrate the interactions between amylin oligomers and non-amyloid β component (NAC) oligomers. Using molecular dynamics simulations and statistical calculations, we studied the mechanisms through which NAC oligomers interact with amylin oligomers to form NAC-amylin hetero-oligomers. Our simulations have shown that there are more than one possible pathways, which form the NAC-amylin hetero-oligomers. Our structural analyses demonstrate that the interactions in the NAC-amylin hetero-oligomers do not affect the structural features of the NAC oligomers, but they do stabilize the structures of the amylin oligomers. Taken together, our results strongly support the hypothesis that NAC oligomers may interact with amylin oligomers through several pathways, of which some pathways are more preferred because of the structural stability of the cross-seeding NAC-amylin oligomers.

ChemInform Abstract: Structural Insights into the Polymorphism of Self‐Assembled Amylin Oligomers

AbstractReview: 43 refs.

Proteasome regulates turnover of toxic human amylin in pancreatic cells.

Toxic human amylin (hA) oligomers and aggregates are implicated in the pathogenesis of type2 diabetes mellitus (T2DM). Although recent studies demonstrated a causal connection between hA uptake and toxicity in pancreatic cells, the mechanism of amylin's clearance following its internalization and its relationship to toxicity is yet to be determined, and hence was investigated here. Using pancreatic rat insulinoma β-cells and human islets as model systems, we show that hA, following its internalization, first accumulates in the cytosol followed by its translocation into nucleus, and to a lesser extent lysosomes, keeping the net cytosolic amylin content low. An increase in hA accumulation in the nucleus of pancreatic cells correlated with its cytotoxicity, suggesting that its excessive accumulation in the nucleus is detrimental. hA interacted with 20S core and 19S lid subunits of the β-cell proteasomal complex, as suggested by immunoprecipitation and confocal microscopy studies, which subsequently resulted in a decrease in the proteasome's proteolytic activity in these cells. Invitro binding and activity assays confirmed an intrinsic and potent ability of amylin to interact with the 20S core complex thereby modulating its proteolytic activity. Interestingly, less toxic and aggregation incapable rat amylin (rA) showed a comparable inhibitory effect on proteasome activity and protein ubiquitination, decoupling amylin aggregation/ toxicity and amylin-induced protein stress. In agreement with these studies, inhibition of proteasomal proteolytic activity significantly increased intracellular amylin content and toxicity. Taken together, our results suggest a pivotal role of proteasomes in amylin's turnover and detoxification in pancreatic cells.

Human amylin proteotoxicity impairs protein biosynthesis, and alters major cellular signaling pathways in the heart, brain and liver of humanized diabetic rat model in vivo.

Chronic hypersecretion of the 37 amino acid amylin is common in type 2 diabetics (T2D). Recent studies implicate human amylin aggregates cause proteotoxicity (cell death induced by misfolded proteins) in both the brain and the heart. Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified. We investigated the metabolic consequences of amyloidogenic and cytotoxic amylin oligomers in heart, brain, liver, and plasma using non-targeted metabolomics analysis in a rat model expressing pancreatic human amylin (HIP model). Four metabolites were significantly different in 3 or more of the the four compartments (heart, brain, liver, and plasma) in HIP rats. When compared to a T2D rat model, HIP hearts uniquely had significant DECREASES in five amino acids (lysine, alanine, tyrosine, phenylalanine, serine), with phenylalanine decreased across all four tissues investigated, including plasma. In contrast, significantly INCREASED circulating phenylalanine is reported in diabetics in multiple recent studies. DECREASED phenylalanine may serve as a unique marker of cardiac and brain dysfunction due to hyperamylinemia that can be differentiated from alterations in T2D in the plasma. While the deficiency in phenylalanine was seen across tissues including plasma and could be monitored, reduced tyrosine was seen only in the brain. The 50% reduction in phenylalanine and tyrosine in HIP brains is significant given their role in supporting brain chemistry as a precursor for catecholamines (dopamine, norepinephrine, epinephrine), which may contribute to the increased morbidity and mortality in diabetics at a multi-system level beyond the effects on glucose metabolism.

Human amylin proteotoxicity impairs protein biosynthesis, and alters major cellular signaling pathways in the heart, brain and liver of humanized diabetic rat model in vivo

The 37 amino acid hormone Amylin is co‐secreted with insulin from β cells in the pancreas. In pre‐diabetic and obese humans, chronic amylin hyper‐secretion parallels the course of disease and is involved in the pathophysiology of beta cell destruction in the pancreas. In rats with transgenic expression of beta cell amylin (HIP), we have discovered that human amylin is prone to misfolding and has proteotoxic effects in vivo, resulting in the induction of cell death paralleling the pathophysiology of neurodegenerative disease. These misfolded proteotoxic amylin proteins are found to migrate to both the brain and heart to induce both neurologic deficits and cardiac dysfunction. In the present study, we use non‐targeted GC‐MS metabolomics analysis to investigate the metabolic consequences of amyloidogenic and cytotoxic amylin oligomers and diabetes in HIP heart, brain, liver, and plasma compared to wild type controls at 1 year of age. We identified that HIP hearts had 45 significantly altered metabolites by t‐test (p<0.05) compared to wildtype control hearts (0.1–34.3 fold different, N=8/group). Similarly, we identified 30 metabolites significantly different in the HIP brain by t‐test (p<0.05) compared to wildtype control brains (0.2–25.2 fold different (N=~10/group). HIP livers had 58 metabolites significantly altered by t‐test (p<0.05) compared to wildtype livers (0.01–99.4 fold different, N=~10/group. Pathway enrichment analysis identified a systemic alteration in protein biosynthesis in the heart and brain of HIP rats compared to wild type controls. Phenylalanine metabolism and aminoacyl‐tRNA biosynthesis were specifically decreased in heart and plasma. Tyrosine metabolism is affected across organs, including decreased tyrosine (heart), phenylalanine (heart, liver, brain), and increased fumarate (heart, liver, brain). Increased urea and urea cycle were identified in heart and liver. As protein degradation is a major up‐regulator of the urea cycle in human rat diabetic models, these findings suggest a broader connection between amylin, diabetes, protein catabolism, and effects on the urea cycle, which may contribute to the increased morbidity and mortality in diabetics at a multi‐system level beyond the effects on glucose metabolism.Support or Funding InformationThis work was supported by the National Institutes of Health (R01HL104129 to M.W.; R01HL118474 to F.D.), a Jefferson‐Pilot Corporation Fellowship (to M.W.), National Science Foundation (CBET 1357600 to F.D.), Alzheimer's Association (VMF‐15‐363458 to F.D.) and the Leducq Foundation (to M.W.).

Structural Insights into the Polymorphism of Self‐Assembled Amylin Oligomers

AbstractType 2 diabetes (T2D) affects over 300 million people worldwide. The main component, found in the pancreas of 95 % of T2D patients, is amylin oligomers and fibrils. So far, four different molecular structures of the self‐assembled amylin oligomers have been observed experimentally: two ssNMR models and two crystal models. This review illustrates that there are further self‐assembled amylin oligomers that differ in the orientations of the side chains along the β‐arch and are all derived from the two ssNMR models. This review focuses on polymorphism of the self‐assembled amylin oligomers. It also provides the various pathway mechanisms which lead to various amylin oligomers. Finally, it illustrates that interactions of amylin oligomers with further amyloids, such as Aβ oligomers, increase the polymorphism by forming polymorphic states of amylin‐Aβ oligomers with various pathway mechanisms. The polymorphism of amylin oligomers and the polymorphism of the cross‐seeding amylin‐Aβ oligomers phenomena could contribute to explaining, at least in part, the still unknown origins of the pathological conditions, and may assist in preventing aggregation in amyloidogenic diseases with drug design and other therapeutic approaches.