Inhibition of hIAPP Amyloid Aggregation and Pancreatic β‐Cell Toxicity by OH‐Terminated PAMAM Dendrimer

Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type‐2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation‐3 OH‐terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT‐1 cells as well as in mouse islets. This finding is supported by high‐throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c‐terminal portion of the peptide, where the amyloidogenic sequence (residues 22–29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self‐association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type‐2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation.     

Mitigation of Amyloidosis with Nanomaterials

Amyloidosis is a biophysical phenomenon of protein aggregation with biological and pathogenic implications. Among the various strategies developed to date, nanomaterials and multifunctional nanocomposites possessing certain structural and physicochemical traits are promising candidates for mitigating amyloidosis in vitro and in vivo. The mechanisms underpinning protein aggregation and toxicity are introduced, and opportunities in materials science to drive this interdisciplinary field forward are highlighted. Advancement of this emerging frontier hinges on exploitation of protein self-assembly and interactions of amyloid proteins with nanoparticles, intracellular and extracellular proteins, chaperones, membranes, organelles, and biometals.     

Nanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules

Understanding how small molecules interface with amyloid fibrils at the nanoscale is of importance for developing therapeutic treatments against amyloid-based diseases. Here, we show for the first time that human islet amyloid polypeptides (IAPP) in the fibrillar form are polymorphic, ambidextrous, and possess multiple periodicities. Upon interfacing with the small molecule epigallocatechin gallate (EGCG), IAPP aggregation was rendered off-pathway and assumed a form with soft and disordered clusters, while mature IAPP fibrils displayed kinks and branching but conserved the twisted fibril morphology. These nanoscale phenomena resulted from competitive interactions between EGCG and the IAPP amyloidogenic region, as well as end capping of the fibrils by the small molecule. This information is crucial in delineating IAPP toxicity implicated in type 2 diabetes and for developing new inhibitors against amyloidogenesis.

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Graphene quantum dots rescue protein dysregulation of pancreatic β-cells exposed to human islet amyloid polypeptide

Nano Research - The amyloid aggregation of peptides and proteins is a hallmark of neurological disorders and type 2 diabetes. Human islet amyloid polypeptide (IAPP), co-secreted with insulin by...     

Amyloid Self‐Assembly of hIAPP8‐20 via the Accumulation of Helical Oligomers, α‐Helix to β‐Sheet Transition,and Formation of β‐Barrel Intermediates

The self‐assembly of human islet amyloid polypeptide (hIAPP) into β‐sheet‐rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N‐terminal residues 8–17 as α‐helices. To understand the contribution of the N‐terminal helix to the aggregation of full‐length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8–20 (hIAPP8‐20) are investigated with combined computational and experimental approaches. hIAPP8‐20 forms cross‐β nanofibrils in silico from isolated helical monomers via the helical oligomers and α‐helices to β‐sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed‐phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass‐spectroscopy study of hIAPP8‐20 aggregation. hIAPP8‐20 oligomers smaller than hexamers are helical and unstable, while the α‐to‐β transition starts from the hexamers. Converted β‐sheet‐rich oligomers first form β‐barrel structures as intermediates before aggregating into cross‐β nanofibrils. This study uncovers a complete picture of hIAPP8‐20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β‐barrel intermediates, and assembly of cross‐β protofibrils, thereby shedding light on the aggregation of full‐length hIAPP, a hallmark of pancreatic beta‐cell degeneration.