We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model).
Thus, the reported study provides a valuable approach to develop polymer-based amyloid inhibitors to suppress the formation of toxic intermediates of β-amyloid-1-40 and amylin.
The characterization of structure ensemble of hIAPP, as well as the differences between hIAPP and its non-amyloidogenic homologous such as rat IAPP (rIAPP), would greatly help to illuminate the amyloidosis mechanism of IAPP.
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.
Recent data have demonstrated the amyloid propensity of murine amylin and the therapeutic analogue pramlintide, suggesting a universality for amylinamyloidosis.
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.
Fmoc-synthesis protocol was applied for the synthesis of IAPP and Lactoferrin whereas Amyloid was synthesized through the Boc-chemistry as early detailed.
We also discuss whether cross-seeding is important in the development of amyloidosis, focusing specifically on the amyloid proteins AA, transthyretin, and islet amyloid polypeptide (IAPP).
In this work, we develop coarse-grained molecular dynamics (CGMD) models to simulate the dynamic self-assembly of two types of amyloids (amylin and amyloid β (Aβ)).
We propose that these insights will aid in designing intervention strategies and novel IAPP analogs for the management of type 2 diabetes, Alzheimer's disease, or other diseases related to IAPP dysfunction or cross-amyloid interactions.
Amyloid fibrils form from spontaneously misfolded amylin, depositing in islet cells to elicit apoptosis, beta cell degeneration and decrease insulin secretion, with amyloidosis affecting up to 80% of pancreatic islet cells in T2D.
Systematic molecular dynamics simulations further provided molecular and structural details for the observed differential effects of proteins on IAPPamyloidosis.
Furthermore, the probe has ~10-fold higher binding affinity towards Aβ aggregates (86nM) compared to commonly used Thioflavin T. Most importantly, CQ probe displays unambiguous selectivity towards Aβ aggregates compared to other toxic protein aggregates such as tau, α-synuclein (α-Syn) and islet amyloid polypeptide (IAPP).
Acute applications of human amylin or Aβ<sub>1-42</sub> resulted in an increase in [Ca<sup>2+</sup>]i that could be blocked by the amylin receptor antagonist, AC253.
Recent studies have identified the amylin receptor as a capable mediator of the deleterious actions of Aβ and furthermore, administration of amylin receptor-based peptides has been shown to improve spatial memory and learning in transgenic mouse models of AD.
Further, C4BP interacts strongly with various types of amyloid and enhances fibrillation of islet amyloid polypeptide secreted from pancreatic beta cells, which may attenuate pro-inflammatory and cytotoxic effects of this amyloid.
Amyloid formation by the neuropancreatic hormone, islet amyloid polypeptide (IAPP or amylin), one of the most amyloidogenic sequences known, leads to islet amyloidosis in type 2 diabetes and to islet transplant failure.
In fact, AD and T2DM have comparable pathological features in the islet and brain (amyloid derived from amyloid β protein (β-amyloid) in the brain in AD and islet amyloid derived from islet amyloid polypeptide in the pancreas in T2DM).
The IAPP-132G/A promoter polymorphism is not associated with T2DM, a requirement for insulin therapy or with the degree of islet amyloidosis in cohorts from the UK or Finland.
The contributions of charged residues as they relate to the amyloid-forming 8-20 sequence were also investigated using IAPP fragments and by assessing the effects of pH and counterions.