Exploiting the Therapeutic Potential of 8-β-d-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid β-Peptide (1–42)

AbstractA critical role of the hormone islet amyloid polypeptide (IAPP) is vividly discussed for Type 2 Diabetes (T2D), where amyloid deposits in pancreatic islets consisting of fibrillar IAPP have been associated with beta cell loss. Here, we applied cryo-electron microscopy to elucidate the structure of IAPP fibrils prepared at physiological pH and reconstructed densities of three dominant polymorphs. An atomic model of the main polymorph comprising residues 13 – 37 in a density map of 4.2 Å resolution reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, which is essential for IAPP amyloidogenicity, forms the protofilament interface together with tyrosine 37 and the amidated C-terminus. The main IAPP fibril polymorph resembles polymorphs of the Alzheimer disease (AD)-associated amyloid-β peptide (Aβ), which is striking in light of the epidemiological link between T2D and AD and reports on IAPP-Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism S20G with the early-onset AD Arctic mutation E22G of Aβ, rationalize previous data on IAPP fibrils, help to elucidate mechanisms of amyloid formation and toxicity, and support the design of fibril growth inhibitors as well as imaging probes for early detection of IAPP fibrils.

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Human Islet Amyloid Polypeptide Fibril Binding to Catalase: A Transmission Electron Microscopy and Microplate Study

The Scientific World JOURNAL ◽

10.1100/tsw.2010.73 ◽

2010 ◽

Vol 10 ◽

pp. 879-893 ◽

Cited By ~ 10

Author(s):

Nathaniel G. N. Milton ◽

J. Robin Harris

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Islet Amyloid Polypeptide ◽

Amyloid Β ◽

Human Islet ◽

Islet Amyloid ◽

Human Islet Amyloid Polypeptide ◽

Transmission Electron

The diabetes-associated human islet amyloid polypeptide (IAPP) is a 37-amino-acid peptide that forms fibrilsin vitroandin vivo. Human IAPP fibrils are toxic in a similar manner to Alzheimer's amyloid-β (Aβ) and prion protein (PrP) fibrils. Previous studies have shown that catalase binds to Aβ fibrils and appears to recognize a region containing the Gly-Ala-Ile-Ile sequence that is similar to the Gly-Ala-Ile-Leu sequence found in human IAPP residues 24-27. This study presents a transmission electron microscopy (TEM)—based analysis of fibril formation and the binding of human erythrocyte catalase to IAPP fibrils. The results show that human IAPP 1-37, 8-37, and 20-29 peptides form fibrils with diverse and polymorphic structures. All three forms of IAPP bound catalase, and complexes of IAPP 1-37 or 8-37 with catalase were identified by immunoassay. The binding of biotinylated IAPP to catalase was high affinity with a KDof 0.77nM, and could be inhibited by either human or rat IAPP 1-37 and 8-37 forms. Fibrils formed by the PrP 118-135 peptide with a Gly-Ala-Val-Val sequence also bound catalase. These results suggest that catalase recognizes a Gly-Ala-Ile-Leu—like sequence in amyloid fibril-forming peptides. For IAPP 1-37 and 8-37, the catalase binding was primarily directed towards fibrillar rather than ribbon-like structures, suggesting differences in the accessibility of the human IAPP 24-27 Gly-Ala-Ile-Leu region. This suggests that catalase may be able to discriminate between different structural forms of IAPP fibrils. The ability of catalase to bind IAPP, Aβ, and PrP fibrils demonstrates the presence of similar accessible structural motifs that may be targets for antiamyloid therapeutic development.

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The antioxidant xanthorrhizol prevents amyloid-β-induced oxidative modification and inactivation of neprilysin

Bioscience Reports ◽

10.1042/bsr20171611 ◽

2018 ◽

Vol 38 (1) ◽

Cited By ~ 6

Author(s):

Chol Seung Lim ◽

Jung-Soo Han

Keyword(s):

Therapeutic Potential ◽

Neuroblastoma Cells ◽

Amyloid Β ◽

Enzymatic Activities ◽

Oxidative Modification ◽

Amyloid Β Peptide ◽

Oxygen Species ◽

Human Neuroblastoma Cells ◽

Neuroprotective Effects ◽

Human Neuroblastoma

Activity of neprilysin (NEP), the major protease which cleaves amyloid-β peptide (Aβ), is reportedly reduced in the brains of patients with Alzheimer’s disease (AD). Accumulation of Aβ generates reactive oxygen species (ROS) such as 4-hydroxynonenal (HNE), and then reduces activities of Aβ-degrading enzymes including NEP. Xanthorrhizol (Xan), a natural sesquiterpenoid, has been reported to possess antioxidant and anti-inflammatory properties. The present study examined the effects of Xan on HNE- or oligomeric Aβ42-induced oxidative modification of NEP protein. Xan was added to the HNE- or oligomeric Aβ42-treated SK-N-SH human neuroblastoma cells and then levels, oxidative modification and enzymatic activities of NEP protein were measured. Increased HNE levels on NEP proteins and reduced enzymatic activities of NEP were observed in the HNE- or oligomeric Aβ42-treated cells. Xan reduced HNE levels on NEP proteins and preserved enzymatic activities of NEP in HNE- or oligomeric Aβ42-treated cells. Xan reduced Aβ42 accumulation and protected neurones against oligomeric Aβ42-induced neurotoxicity through preservation of NEP activities. These findings indicate that Xan possesses therapeutic potential for the treatment of neurodegenerative diseases, including AD, and suggest a potential mechanism for the neuroprotective effects of antioxidants for the prevention of AD.

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NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1718819115 ◽

2018 ◽

Vol 115 (8) ◽

pp. E1876-E1885 ◽

Cited By ~ 116

Author(s):

Yujun Hou ◽

Sofie Lautrup ◽

Stephanie Cordonnier ◽

Yue Wang ◽

Deborah L. Croteau ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Hippocampal Neurons ◽

Therapeutic Potential ◽

Neuronal Degeneration ◽

Amyloid Β ◽

Synaptic Dysfunction ◽

Amyloid Β Peptide ◽

Repair Deficiency ◽

Dna Repair Deficiency

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ+/− mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ+/− mice have a reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ+/− mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ+/− mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ+/− mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have therapeutic potential for AD.

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Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

Physical Chemistry Chemical Physics ◽

10.1039/c7cp05695h ◽

2017 ◽

Vol 19 (41) ◽

pp. 28414-28423 ◽

Cited By ~ 19

Author(s):

Yunxiang Sun ◽

Bo Wang ◽

Xinwei Ge ◽

Feng Ding

Keyword(s):

Amyloid Beta ◽

Islet Amyloid Polypeptide ◽

Amyloid Β ◽

Islet Amyloid

The amyloid core sequences of amyloid-β (Aβ) and islet amyloid polypeptide (IAPP), Aβ16–22 and IAPP22–28, feature distinct aggregation free landscape.

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Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors

Journal of Biological Chemistry ◽

10.1074/jbc.m117.806109 ◽

2017 ◽

Vol 293 (8) ◽

pp. 2888-2902 ◽

Cited By ~ 25

Author(s):

Pascal Krotee ◽

Sarah L. Griner ◽

Michael R. Sawaya ◽

Duilio Cascio ◽

Jose A. Rodriguez ◽

...

Keyword(s):

Islet Amyloid Polypeptide ◽

Amyloid Β ◽

Human Islet ◽

Islet Amyloid ◽

Human Islet Amyloid Polypeptide

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Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate

eLife ◽

10.7554/elife.31226 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 35

Author(s):

Diana C Rodriguez Camargo ◽

Kyle J Korshavn ◽

Alexander Jussupow ◽

Kolio Raltchev ◽

David Goricanec ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Death ◽

Islet Amyloid Polypeptide ◽

Amyloid Β ◽

Md Simulations ◽

Human Islet ◽

Amyloid Formation ◽

Islet Amyloid ◽

Induce Cell Death

Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

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Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

Biomolecules ◽

10.3390/biom10010134 ◽

2020 ◽

Vol 10 (1) ◽

pp. 134 ◽

Cited By ~ 1

Author(s):

Anna L. Gharibyan ◽

Tohidul Islam ◽

Nina Pettersson ◽

Solmaz A. Golchin ◽

Johanna Lundgren ◽

...

Keyword(s):

Apolipoprotein E ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Amyloid Formation ◽

Loss Of Function ◽

Islet Amyloid ◽

Amyloid Deposits ◽

Primary Focus ◽

The Impact

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

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