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Journal of Chemical Theory and... Aug 2020Motivated by the role that amylin aggregates play in type-II diabetes, we compare the stability of regular amylin fibrils with the stability of fibrils where l-amino...
Motivated by the role that amylin aggregates play in type-II diabetes, we compare the stability of regular amylin fibrils with the stability of fibrils where l-amino acid chains are replaced by d-retro inverso (DRI) amylin, that is, peptides where the sequence of amino acids is reversed, and at the same time, the l-amino acids are replaced by their mirror images. Our molecular dynamics simulations show that despite leading to only a marginal difference in the fibril structure and stability, aggregating DRI-amylin peptides have different patterns of contacts and hydrogen bonding. Because of these differences, DRI-amylin, when interacting with regular (l) amylin, alters the elongation process and lowers the stability of hybrid amylin fibrils. Our results not only suggest the potential use of DRI-amylin as an inhibitor of amylin fibril formation but also point to the possibility of using the insertion of DRI proteins in l-assemblies as a way to probe the role of certain kinds of hydrogen bonds in supramolecular assemblies or aggregates.
Topics: Humans; Islet Amyloid Polypeptide; Molecular Dynamics Simulation; Protein Stability
PubMed: 32667784
DOI: 10.1021/acs.jctc.0c00523 -
International Journal of Molecular... Apr 2022The localization and expression of amylin protein in the rodent brain and mouse neuroblastoma Neuro-2a (N2a) are less widely known. Thus, this study investigated the...
The localization and expression of amylin protein in the rodent brain and mouse neuroblastoma Neuro-2a (N2a) are less widely known. Thus, this study investigated the expression distribution of amylin in the rat brain and N2a treated with steroid hormones. Amylin protein was identified in the olfactory bulb, cerebral cortex, dentate gyrus, thalamus, hypothalamus, ventral tegmental area (VTA), cerebellum, and brain stem in the rat brain. Additionally, the amylin protein was localized with the mature neurons of the cerebral cortex and dopaminergic neurons of the VTA. Progesterone (P4) and dexamethasone (Dex) significantly decreased, and 17β-estradiol (E2) increased the amylin protein level in the cerebral cortex. The P4 receptor antagonist RU486 significantly influenced the effects of P4 and Dex, and the E2 receptor antagonist ICI 182,780 slightly changed E2's effect. Amylin protein expression was significantly reduced in the VTA by P4 and Dex, and its expression was changed only following P4 plus RU486 treatment. It was confirmed for the first time that amylin protein is strongly expressed in the cytoplasm in N2a cells using immunofluorescent staining. P4 increased the levels of amylin, and RU486 treatment decreased them. Dex significantly increased the levels of amylin protein. RU486 treatment reversed the effects of Dex. Therefore, amylin protein is expressed in the cerebral cortex neurons and dopaminergic neurons of the VTA of the immature rat brain. P4 and Dex influence the expression of amylin protein in the rat brain and N2a cells.
Topics: Animals; Brain; Estradiol; Islet Amyloid Polypeptide; Mice; Mifepristone; Progesterone; Rats
PubMed: 35457166
DOI: 10.3390/ijms23084348 -
Neuroscience Jul 2017G-protein-coupled receptors (GPCRs) are shown to be involved in Alzheimer's disease (AD) pathogenesis. However, because GPCRs include a large family of membrane... (Review)
Review
G-protein-coupled receptors (GPCRs) are shown to be involved in Alzheimer's disease (AD) pathogenesis. However, because GPCRs include a large family of membrane receptors, it is unclear which specific GPCR or pathway with rational ligands can become effective therapeutic targets for AD. Amylin receptor (AmR) is a GPCR that mediates several activities, such as improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reactions and potentially enhancing neural regeneration. Recent studies show that peripheral treatments with amylin or its clinical analog, pramlintide, reduced several components of AD pathology, including amyloid plaques, tauopathy, neuroinflammation and other components in the brain, corresponding with improved learning and memory in AD mouse models. Because amylin shares a similar secondary structure with amyloid-β peptide (Aβ), I propose that the AmR/GPCR pathway is disturbed by a large amount of Aβ in the AD brain, leading to tau phosphorylation, neuroinflammation and neuronal death in the pathological cascade. Amylin-type peptides, readily crossing the blood-brain barrier (BBB), are the rational ligands to enhance this GPCR pathway and may exhibit utility as novel therapeutic agents for treating AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Islet Amyloid Polypeptide; Receptors, Islet Amyloid Polypeptide
PubMed: 28528968
DOI: 10.1016/j.neuroscience.2017.05.024 -
Physiology & Behavior Jul 2010Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a... (Review)
Review
Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a direct action at the area postrema (AP) via amylin receptors that are heterodimers of the calcitonin receptor core protein with a receptor activity modifying protein. Peripheral amylin leads to accumulation of cyclic guanosine monophosphate, phosphorylated extracellular-signal regulated kinase 1/2 and c-Fos protein in AP neurons. The particular amylin-activated AP neurons mediating its anorexigenic action seem to be noradrenergic. The central pathways mediating amylin's effects have been characterized by lesioning and tracing studies, identifying important connections from the AP to the nucleus of the solitary tract and lateral parabrachial nucleus. Amylin was shown to interact, probably at the brainstem, with other signals involved in the short term control of food intake, namely cholecystokinin, glucagon-like peptide 1 and peptide YY. Amylin also interacts with the adiposity signal leptin; this interaction, which is thought to involve the hypothalamus, may have important implications for the development of new and improved hormonal obesity treatments. In conclusion, amylin actions on food intake seem to reside primarily within the brainstem, and the associated mechanisms are starting to be unraveled. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
Topics: Amyloid; Animals; Anorexia; Appetite Depressants; Brain Stem; Eating; Humans; Islet Amyloid Polypeptide; Neurons; Signal Transduction
PubMed: 20226802
DOI: 10.1016/j.physbeh.2010.03.001 -
The Journal of Infectious Diseases Apr 2021Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that...
BACKGROUND
Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Thus, we determined if VZV central nervous system infection produces amyloid.
METHODS
Aβ peptides, amylin, and amyloid were measured in cerebrospinal fluid (CSF) from 16 VZV vasculopathy subjects and 36 stroke controls. To determine if infection induced amyloid deposition, mock- and VZV-infected quiescent primary human perineurial cells (qHPNCs), present in vasculature, were analyzed for intracellular amyloidogenic transcripts/proteins and amyloid. Supernatants were assayed for amyloidogenic peptides and ability to induce amyloid formation. To determine amylin's function during infection, amylin was knocked down with small interfering RNA and viral complementary DNA (cDNA) was quantitated.
RESULTS
Compared to controls, VZV vasculopathy CSF had increased amyloid that positively correlated with amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. Intracellular amylin, Aβ42, and amyloid were seen only in VZV-infected qHPNCs. VZV-infected supernatant formed amyloid fibrils following addition of amyloidogenic peptides. Amylin knockdown decreased viral cDNA.
CONCLUSIONS
VZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV vasculopathy. In addition, we identified a novel proviral function of amylin.
Topics: Amyloid; Amyloid beta-Peptides; Arteritis; DNA, Complementary; DNA, Viral; Herpes Zoster; Herpesvirus 3, Human; Humans; Islet Amyloid Polypeptide; Peptide Fragments; Stroke
PubMed: 32809013
DOI: 10.1093/infdis/jiaa513 -
American Journal of Physiology.... Feb 2016Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred...
Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO (125)I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80-90% in 4-wk-old male DR rats reduced their ARC and VMN (125)I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Eating; Glucose Intolerance; Insulin Resistance; Iodine Radioisotopes; Islet Amyloid Polypeptide; Leptin; Male; Obesity; RNA, Small Interfering; Radionuclide Imaging; Rats; Receptors, Calcitonin; STAT3 Transcription Factor; Ventromedial Hypothalamic Nucleus; Weight Gain
PubMed: 26676252
DOI: 10.1152/ajpregu.00462.2015 -
Cellular and Molecular Life Sciences :... Jun 2012Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and... (Review)
Review
Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.
Topics: Adiposity; Animals; Anti-Obesity Agents; Brain Stem; Energy Metabolism; Female; Gastric Emptying; Homeostasis; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Obesity; Rats; Receptors, Islet Amyloid Polypeptide; Satiation
PubMed: 22193913
DOI: 10.1007/s00018-011-0905-1 -
Molecular Metabolism Feb 2018Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. One of its best-characterized effects is the reduction in eating and... (Review)
Review
BACKGROUND
Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. One of its best-characterized effects is the reduction in eating and body weight seen in preclinical and clinical studies. Amylin activates specific receptors, a portion of which it shares with calcitonin gene-related peptide (CGRP). Amylin's role in the control of energy metabolism relates to its satiating effect, but recent data indicate that amylin may also affect hedonic aspects in the control of eating, including a reduction of the rewarding value of food. Recently, several amylin-based peptides have been characterized. Pramlintide (Symlin) is currently the only one being used clinically to treat type 1 and type 2 diabetes. However other amylin analogs with improved pharmacokinetic properties are being considered as anti-obesity treatment strategies. Several other studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.
SCOPE OF REVIEW
This review will briefly summarize amylin physiology and pharmacology and then focus on amylin's role in food reward and the effects of amylin analogs in pre-clinical testing for anti-obesity drugs.
CONCLUSION
We propose here that the effects of amylin may be homeostatic and hedonic in nature.
Topics: Animals; Anti-Obesity Agents; Brain Stem; Humans; Hyperphagia; Islet Amyloid Polypeptide; Obesity; Peptide Fragments; Reward
PubMed: 29203236
DOI: 10.1016/j.molmet.2017.11.009 -
Communications Biology Jan 2023Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes....
Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology.
Topics: Humans; Rats; Animals; Islet Amyloid Polypeptide; Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Pancreas; Inflammation
PubMed: 36596993
DOI: 10.1038/s42003-022-04398-2 -
Molecules (Basel, Switzerland) Feb 2022Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often... (Review)
Review
Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells demise in diabetics. The unifying mechanism by which amyloid proteins, including hIAPP, aggregate and kill cells is still matter of debate. The pathology of type-2 diabetes mellitus (T2DM) is characterized by extracellular and intracellular accumulation of toxic hIAPP species, soluble oligomers and insoluble fibrils in pancreatic human islets, eventually leading to loss of β-cell mass. This review focuses on molecular, biochemical and cell-biology studies exploring molecular mechanisms of hIAPP synthesis, trafficking and degradation in the pancreas. In addition to hIAPP turnover, the dynamics and the mechanisms of IAPP-membrane interactions; hIAPP aggregation and toxicity in vitro and in situ; and the regulatory role of diabetic factors, such as lipids and cholesterol, in these processes are also discussed.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Pancreas; Protein Aggregates; Protein Aggregation, Pathological; Protein Conformation; Protein Folding; Proteostasis Deficiencies
PubMed: 35164285
DOI: 10.3390/molecules27031021