Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice

Abstract Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation in vitro. We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition in vivo. hIAPP transgenic mice were crossed with Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/Δ3), and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/Δ3 mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP;Hspg2Δ3/Δ3 mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition in vivo through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.

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Intraocular in vivo imaging of pancreatic islet cell physiology/pathology

Molecular Metabolism ◽

10.1016/j.molmet.2017.03.014 ◽

2017 ◽

Vol 6 (9) ◽

pp. 1002-1009 ◽

Cited By ~ 16

Author(s):

Ingo B. Leibiger ◽

Per-Olof Berggren

Keyword(s):

Pancreatic Islet ◽

In Vivo Imaging ◽

Islet Cell ◽

Cell Physiology ◽

Pancreatic Islet Cell

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Binding and safety profile of novel benzoxazole derivative for in vivo imaging of amyloid deposits in Alzheimer's disease

Geriatrics and Gerontology International ◽

10.1111/j.1447-0594.2007.00430.x ◽

2007 ◽

Vol 7 (4) ◽

pp. 393-400 ◽

Cited By ~ 5

Author(s):

Nobuyuki Okamura ◽

Shozo Furumoto ◽

Yoshihito Funaki ◽

Takahiro Suemoto ◽

Motohisa Kato ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Safety Profile ◽

In Vivo Imaging ◽

Amyloid Deposits

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In vivo proliferation of differentiated pancreatic islet beta cells in transgenic mice expressing mutated cyclin-dependent kinase 4

Diabetologia ◽

10.1007/s00125-004-1522-4 ◽

2004 ◽

Vol 47 (10) ◽

pp. 1819-1830 ◽

Cited By ~ 15

Author(s):

S. Hino ◽

T. Yamaoka ◽

Y. Yamashita ◽

T. Yamada ◽

J. Hata ◽

...

Keyword(s):

Transgenic Mice ◽

Beta Cells ◽

Pancreatic Islet ◽

Cyclin Dependent Kinase ◽

Islet Beta Cells ◽

Pancreatic Islet Beta Cells

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Amyloid damage to islet β-cells in type 2 diabetes: hypoxia or pseudo-hypoxia?

10.1101/810747 ◽

2019 ◽

Cited By ~ 2

Author(s):

Vittorio Bellotti ◽

Alessandra Corazza ◽

Beatrice Foglia ◽

Erica Novo ◽

J. Paul Simons ◽

...

Keyword(s):

Type 2 Diabetes ◽

Amyloid Deposition ◽

Β Cells ◽

Islet Amyloid ◽

Good Tool ◽

Amyloid Deposits ◽

Oxygen Perfusion

ABSTRACTAggregation of islet amyloid polypeptide (IAPP) and amyloid deposition in the islets of Langerhans may significantly contribute to the multifactorial pathogenic mechanisms leading to type 2 diabetes. A direct toxic effect on β-cells of oligomeric IAAP has been demonstrated in in vitro models, but the mechanism operating in vivo is still unclear. Mice models presenting amyloid deposition and glucose intolerance represent a good tool for exploring in vivo a putative mechanism of toxicity directly related to the physical expansion of the extracellular matrix by the amyloid fibrillar aggregates. Based on our hypothesis that deposition of amyloid may influence the oxygen perfusion, we have calculated that the mean distribution of oxygen partial pressure would drop by more than 50 % in the presence of amyloid deposits in the islet. This condition of hypoxia caused by the remodelling of the extracellular space may explain the metabolic abnormalities in the Langerhans islets, otherwise interpreted as pseudo-hypoxic response to IAPP oligomers.

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Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer’s Mouse Model

Frontiers in Neuroscience ◽

10.3389/fnins.2021.803927 ◽

2022 ◽

Vol 15 ◽

Author(s):

Aline Freyssin ◽

Agnès Rioux Bilan ◽

Bernard Fauconneau ◽

Laurent Galineau ◽

Sophie Serrière ◽

...

Keyword(s):

Transgenic Mice ◽

Cognitive Status ◽

Morris Water Maze Test ◽

Enzyme Linked Immunosorbent Assay ◽

Wild Type ◽

Pet Tracer ◽

Amyloid Deposits ◽

Polyethylene Glycol 200 ◽

Amyloid Load

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1β were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.

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Anti-Inflammatory and Reactive Oxygen Species Suppression through Aspirin Pretreatment to Treat Hyperoxia-Induced Acute Lung Injury in NF-κB–Luciferase Inducible Transgenic Mice

Antioxidants ◽

10.3390/antiox9050429 ◽

2020 ◽

Vol 9 (5) ◽

pp. 429 ◽

Cited By ~ 2

Author(s):

Chuan-Mu Chen ◽

Yu-Tang Tung ◽

Chi-Hsuan Wei ◽

Po-Ying Lee ◽

Wei Chen

Keyword(s):

Reactive Oxygen Species ◽

Acute Lung Injury ◽

Lung Injury ◽

Transgenic Mice ◽

In Vivo Imaging ◽

Reactive Oxygen ◽

Luciferase Expression ◽

Oxygen Species ◽

Anti Inflammatory

Acute lung injury (ALI), a common cause of morbidity and mortality in intensive care units, results from either direct intra-alveolar injury or indirect injury following systemic inflammation and oxidative stress. Adequate tissue oxygenation often requires additional supplemental oxygen. However, hyperoxia causes lung injury and pathological changes. Notably, preclinical data suggest that aspirin modulates numerous platelet-mediated processes involved in ALI development and resolution. Our previous study suggested that prehospital aspirin use reduced the risk of ALI in critically ill patients. This research uses an in vivo imaging system (IVIS) to investigate the mechanisms of aspirin’s anti-inflammatory and antioxidant effects on hyperoxia-induced ALI in nuclear factor κB (NF-κB)–luciferase transgenic mice. To define mechanisms through which NF-κB causes disease, we developed transgenic mice that express luciferase under the control of NF-κB, enabling real-time in vivo imaging of NF-κB activity in intact animals. An NF-κB-dependent bioluminescent signal was used in transgenic mice carrying the luciferase genes to monitor the anti-inflammatory effects of aspirin. These results demonstrated that pretreatment with aspirin reduced luciferase expression, indicating that aspirin reduces NF-κB activation. In addition, aspirin reduced reactive oxygen species expression, the number of macrophages, neutrophil infiltration and lung edema compared with treatment with only hyperoxia treatment. In addition, we demonstrated that pretreatment with aspirin significantly reduced the protein levels of phosphorylated protein kinase B, NF-κB and tumor necrosis factor α in NF-κB–luciferase+/+ transgenic mice. Thus, the effects of aspirin on the anti-inflammatory response and reactive oxygen species suppressive are hypothesized to occur through the NF-κB signaling pathway. This study demonstrated that aspirin exerts a protective effect for hyperoxia-induced lung injury and thus is currently the drug conventionally used for hyperoxia-induced lung injury.

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