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name:Abedini, Andisheh

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48


Analysis of Baboon IAPP Provides Insight into Amyloidogenicity and Cytotoxicity of Human IAPP

Ridgway, Zachary; Lee, Kyung-Hoon; Zhyvoloup, Alexander; Wong, Amy; Eldrid, Charles; Hannaberry, Eleni; Thalassinos, Konstantinos; Abedini, Andisheh; Raleigh, Daniel P
The polypeptide hormone islet amyloid polypeptide (IAPP) forms islet amyloid in type 2 diabetes, a process which contributes to pancreatic β-cell dysfunction and death. Not all species form islet amyloid, and the ability to do so correlates with the primary sequence. Humans form islet amyloid, but baboon IAPP has not been studied. The baboon peptide differs from human IAPP at three positions containing K1I, H18R, and A25T substitutions. The K1I substitution is a rare example of a replacement in the N-terminal region of amylin. The effect of this mutation on amyloid formation has not been studied, but it reduces the net charge, and amyloid prediction programs suggest that it should increase amyloidogenicity. The A25T replacement involves a nonconservative substitution in a region of IAPP that is believed to be important for aggregation, but the effects of this replacement have not been examined. The H18R point mutant has been previously shown to reduce aggregation in vitro. Baboon amylin forms amyloid on the same timescale as human amylin in vitro and exhibits similar toxicity toward cultured β-cells. The K1I replacement in human amylin slightly reduces toxicity, whereas the A25T substitution accelerates amyloid formation and enhances toxicity. Photochemical cross-linking reveals that the baboon amylin, like human amylin, forms low-order oligomers in the lag phase of amyloid formation. Ion-mobility mass spectrometry reveals broadly similar gas phase collisional cross sections for human and baboon amylin monomers and dimers, with some differences in the arrival time distributions. Preamyloid oligomers formed by baboon amylin, but not baboon amylin fibers, are toxic to cultured β-cells. The toxicity of baboon oligomers and lack of significantly detectable toxicity with exogenously added amyloid fibers is consistent with the hypothesis that preamyloid oligomers are the most toxic species produced during IAPP amyloid formation.
PMID: 32105649
ISSN: 1542-0086
CID: 4323582

Amyloidogenicity, Cytotoxicity and Receptor Activity of Bovine Amylin; Implications for Xenobiotic Transplantation and the Design of Non-toxic Amylin Variants

Akter, Rehana; Bower, Rebekah L; Abedini, Andisheh; Schmidt, Ann Marie; Hay, Debbie L; Raleigh, Daniel P
Islet amyloid formation contributes to β-cell death and dysfunction in type-2 diabetes and to the failure of islet transplants. Amylin (Islet amyloid polypeptide, IAPP), a normally soluble 37 residue polypeptide hormone produced in the pancreatic β-cells, is responsible for amyloid formation in type-2 diabetes. The peptide is deficient in type-1 diabetes. Amylin normally plays an adaptive role in metabolism and the development of non-toxic, non-amyloidogenic, bioactive variants of human amylin are of interest for use as adjuncts to insulin therapy. Naturally occurring non-amyloidogenic variants are of interest for xenobiotic transplantation and because they can provide clues towards understanding the amyloidogenicity of human amylin. The sequence of amylin is well conserved among species, but sequence differences strongly correlate with in vitro amyloidogenicity and with islet amyloid formation in vivo. Bovine amylin differs from the human peptide at ten positions and is one of the most divergent among known amylin sequences. We show that bovine amylin oligomerizes, but is not toxic to cultured β-cells and is considerably less amyloidogenic than the human polypeptide and is only a low potency agonist at human amylin-responsive receptors. The bovine sequence contains several non-conservative substitutions relative to human amylin including His to Pro, Ser to Pro and Asn to Lys replacements. The effect of these substitutions is analyzed in the context of wild type human amylin; the results provide insight into their role in receptor activation, the mode of assembly of human amylin and into the design of soluble amylin analogs.
PMID: 30086232
ISSN: 1554-8937
CID: 3236252

The Receptor for Advanced Glycation Endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and Exploiting Common Ground for Novel Amyloidosis Therapies

Abedini, Andisheh; Derk, Julia; Schmidt, Ann Marie
Proteotoxicity plays a key role in many devastating human disorders, including Alzheimer's, Huntington's and Parkinson's diseases; type 2 diabetes; systemic amyloidosis; and cardiac dysfunction, to name a few. The cellular mechanisms of proteotoxicity in these disorders have been the focus of considerable research, but their role in prevalent and morbid disorders, such as diabetes, is less appreciated. There is a large body of literature on the impact of glucotoxicity and lipotoxicity on insulin-producing pancreatic β-cells, and there is increasing recognition that proteotoxicty plays a key role. Pancreatic islet amyloidosis by the hormone IAPP, the production of advanced glycation endproducts, and insulin misprocessing into cytotoxic aggregates are all sources of β-cell proteotoxicity in diabetes. Advanced glycation endproducts, produced by the reaction of reducing sugars with proteins and lipids are ligands for the receptor for advanced glycation endproducts (RAGE), as are the toxic pre-fibrillar aggregates of IAPP produced during amyloid formation. The mechanisms of amyloid formation by IAPP in vivo or in vitro are not well understood, and the cellular mechanisms of IAPP-induced β-cell death are not fully defined. Here, we review recent findings that illuminate the factors and mechanisms involved in β-cell proteotoxicity in diabetes. Together, these new insights have far-reaching implications for the establishment of unifying mechanisms by which pathological amyloidoses imbue their injurious effects in vivo.
PMCID:6032365
PMID: 29664151
ISSN: 1469-896x
CID: 3043032

Analysis of the role of the conserved disulfide in amyloid formation by human IAPP in homogenous and heterogeneous environments

Ridgway, Zachary; Zhang, Xiaoxue; Wong, Amy G; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P
Human islet amyloid polypeptide (hIAPP) is a hormone secreted from β-cells in the Islets of Langerhans in response to the same stimuli that lead to insulin secretion. hIAPP plays an adaptive role in glucose homeostasis, but misfolds to form insoluble, fibrillar aggregates in type-II diabetes that are associated with the disease. Along the misfolding pathway, hIAPP forms species that are toxic to β-cells, resulting in reduced β-cell mass. hIAPP contains a strictly conserved disulfide bond between residues 2-7, which forms a small loop at the N-terminus of the molecule. The loop is located outside of the cross β-core in all models of the hIAPP amyloid fibrils. Mutations in this region are rare, and the disulfide loop plays a role in receptor binding, but the contribution of this region to the aggregation of hIAPP is not well understood. We define the role of the disulfide by analyzing a collection of analogues that remove the disulfide, by mutation of Cys to Ser, by reduction and modification of the Cys residues, or by deletion of the first seven residues. The cytotoxic properties of hIAPP are retained in the Cys to Ser disulfide free mutant. Removal of the disulfide bond accelerates amyloid formation in all constructs, both in solution and in the presence of model membranes. Removal of the disulfide reduces the ability of hIAPP to induce leakage of vesicles made up of POPS and POPC. Smaller effects are observed with vesicle that contain 40 mole percent cholesterol, although N-terminal truncation still reduces leakage.
PMCID:6009826
PMID: 29697253
ISSN: 1520-4995
CID: 3057852

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

Abedini, Andisheh; Cao, Ping; Plesner, Annette; Zhang, Jinghua; He, Meilun; Derk, Julia; Patil, Sachi A; Rosario, Rosa; Lonier, Jacqueline; Song, Fei; Koh, Hyunwook; Li, Huilin; Raleigh, Daniel P; Schmidt, Ann Marie
Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis-induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP-induced (h-IAPP-induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand-binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP-induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.
PMCID:5785261
PMID: 29337308
ISSN: 1558-8238
CID: 2916152

Diaphanous 1 (DIAPH1) is Highly Expressed in the Aged Human Medial Temporal Cortex and Upregulated in Myeloid Cells During Alzheimer's Disease

Derk, Julia; Bermudez Hernandez, Keria; Rodriguez, Moises; He, Meilun; Koh, Hyunwook; Abedini, Andisheh; Li, Huilin; Fenyo, David; Schmidt, Ann Marie
BACKGROUND:The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed. OBJECTIVE:To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. METHODS:We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. RESULTS:We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. DISCUSSION/CONCLUSIONS:Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.
PMCID:6082178
PMID: 29966194
ISSN: 1875-8908
CID: 3197542

Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears?

Akter, Rehana; Abedini, Andisheh; Ridgway, Zachary; Zhang, Xiaoxue; Kleinberg, Joel; Schmidt, Ann Marie; Raleigh, Daniel P
Much of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid-rich diet without deleterious metabolic consequences. In contrast, transgenic rodents expressing the human neuropancreatic polypeptide hormone amylin develop hyperglycemia and extensive pancreatic islet amyloid when fed a high fat diet. The process of islet amyloid formation by human amylin contributes to β-cell dysfunction and loss of β-cell mass in type-2 diabetes. We show that ursine amylin is considerably less amyloidogenic and less toxic to β-cells than human amylin, consistent with the hypothesis that part of the adaptation of bears to metabolic challenges might include protection from islet amyloidosis-induced β-cell toxicity. Ursine and human amylin differ at four locations: H18R, S20G, F23L, and S29P. These are interesting from a biophysical perspective since the S20G mutation accelerates amyloid formation but the H18R slows it. An H18RS20G double mutant of human amylin behaves similarly to the H18R mutant, indicating that the substitution at position 18 dominates the S20G replacement. These data suggest one possible mechanism underpinning the protection of bears against metabolic challenges and provide insight into the design of soluble analogs of human amylin.
PMCID:6018008
PMID: 29955200
ISSN: 0021-2148
CID: 3185762

A new mechanism of pancreatic beta-cell toxicity in type 2 diabetes [Meeting Abstract]

Abedini, Andisheh; Plesner, Annette; Cao, Ping; Zhang, Jinghua; Middleton, Chris T; Sartori, Daniel; Derk, Julia; Rosario, Rosa; Song, Fei; Lonier, Jacqueline; Zanni, Martin T; Raleigh, Daniel P; Schmidt, Ann Marie
ISI:000387152400003
ISSN: 1469-896x
CID: 2734192

Amyloidogenicity and Cytotoxicity of Bovine Amylin; Implications for Xenobiotic Transplantation and the Design of Non-toxic Amylin Variants [Meeting Abstract]

Akter, Rehana; Abedini, Andisheh; Bower, Rebekah L; Schmidt, Ann Marie; Hay, Debbie L; Raleigh, Daniel P
ISI:000387152400004
ISSN: 1469-896x
CID: 2734202

Characterizing Pre-Amyloid Oligomers of hIAPP with a Photoinduced Cross-linking Technique [Meeting Abstract]

Ridgway, Zachary; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P
ISI:000387152400016
ISSN: 1469-896x
CID: 2734212