K114 (<i>trans, trans</i>)‐bromo‐2,5‐bis(4‐hydroxystyryl)benzene is an efficient detector of cationic amyloid fibrils

Selmani, Veli; Robbins, Kevin J.; Ivancic, Valerie A.; Lazo, Noel D.

doi:10.1002/pro.2620

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…Together, our CD, TEM, and ThT fluorescence results show that α-helical insulin at pH 2.0 when heated at 60 °C undergoes conformational rearrangement to form cross-β-sheet-containing fibrillar assemblies that bind ThT, consistent with previous reports by us and others. 10,11,15,43,44 In sharp contrast, insulin (30 μM, pH 2) incubated in the presence of RA present in a 1:1 ratio (mol RA:mol insulin) remained α-helical after heating at 60 °C for 7 days (Figure 3C), indicating that RA prevents the α-helix to βsheet conformational rearrangement associated with fibril formation. Additionally, the ratio [θ] 222 /[θ] 208 in all spectra recorded after heating is 0.68 ± 0.02, indicating that insulin remains a dimer.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

Mechanistic Studies of the Inhibition of Insulin Fibril Formation by Rosmarinic Acid

Zheng

Lazo

2018

J. Phys. Chem. B

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The self-assembly of insulin to form amyloid fibrils has been widely studied because it is a significant problem in the medical management of diabetes and is an important model system for the investigation of amyloid formation and its inhibition. A few inhibitors of insulin fibrillation have been identified with potencies that could be higher. Knowledge of how these work at the molecular level is not known but important for the development of more potent inhibitors. Here we show that rosmarinic acid completely inhibits amyloid formation by dimeric insulin at pH 2 and 60 °C. In contrast to other polyphenols, rosmarinic acid is soluble in water and does not degrade at elevated temperatures, and thus we were able to decipher the mechanism of inhibition by a combination of solution-state H NMR spectroscopy and molecular docking. On the basis ofH chemical shift perturbations, intermolecular nuclear Overhauser effect enhancements between rosmarinic acid and specific residues of insulin, and slowed dynamics of rosmarinic acid in the presence of insulin, we show that rosmarinic acid binds to a pocket found on the surface of each insulin monomer. This results in the formation of a mixed tetramolecular aromatic network on the surface of insulin dimer, resulting in increased resistance of the amyloidogenic protein to thermal unfolding. This finding opens new avenues for the design of potent inhibitors of amyloid formation and provides strong experimental evidence for the role of surface aromatic clusters in increasing the thermal stability of proteins.

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Section: ■ Results and Discussionmentioning

confidence: 98%

Mechanistic Studies of the Inhibition of Insulin Fibril Formation by Rosmarinic Acid

Zheng

Lazo

2018

J. Phys. Chem. B

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“…Amongst them, K114 was most informative because of its ability to emit different spectra in each and within plaques. K114 is a Congo red analogue and exhibits an increase in fluorescence intensity when bound to amyloid fibrils at neutral pH [ 17 , 33 ] and spectral shifts in both excitation and emission upon binding to amyloid at high pH (>pH 9.5) [ 33 ]. At pH 10.5, K114 tends to form a highly fluorescent phenolate species with fibrils, and for this reason we used an alkaline pH in our experiments.…”

Section: Discussionmentioning

confidence: 99%

Axonal and myelinic pathology in 5xFAD Alzheimer’s mouse spinal cord

et al. 2017

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As an extension of the brain, the spinal cord has unique properties which could allow us to gain a better understanding of CNS pathology. The brain and cord share the same cellular components, yet the latter is simpler in cytoarchitecture and connectivity. In Alzheimer’s research, virtually all focus is on brain pathology, however it has been shown that transgenic Alzheimer’s mouse models accumulate beta amyloid plaques in spinal cord, suggesting that the cord possesses the same molecular machinery and conditions for plaque formation. Here we report a spatial-temporal map of plaque load in 5xFAD mouse spinal cord. We found that plaques started to appear at 11 weeks, then exhibited a time dependent increase and differential distribution along the cord. More plaques were found in cervical than other spinal levels at all time points examined. Despite heavy plaque load at 6 months, the number of cervical motor neurons in 5xFAD mice is comparable to wild type littermates. On detailed microscopic examination, fine beta amyloid-containing and beta sheet-rich thread-like structures were found in the peri-axonal space of many axons. Importantly, these novel structures appear before any plaque deposits are visible in young mice spinal cord and they co-localize with axonal swellings at later stages, suggesting that these thread-like structures might represent the initial stages of plaque formation, and could play a role in axonal damage. Additionally, we were able to demonstrate increasing myelinopathy in aged 5xFAD mouse spinal cord using the lipid probe Nile Red with high resolution. Collectively, we found significant amyloid pathology in grey and white matter of the 5xFAD mouse spinal cord which indicates that this structure maybe a useful platform to study mechanisms of Alzheimer’s pathology and disease progression.

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“…This process of amyloid-induced cell death is implicated in the loss of neuronal cells by the aggregating amyloid-b (Ab) and other amyloid proteins in Alzheimer's disease and in the killing of insulin-producing islet cells by islet amyloid polypeptide (IAPP, or also known as amylin). 13,26,27 SEVI precursors also showed nucleationdependent two-step amyloid formation under several different conditions 6,[28][29][30][31][32][33] ; however, much still remains to be investigated, for instance, detailed aggregation kinetic analysis and cross-seeding effects on SEVI amyloid formation. Atomistic and secondary structure and morphology of SEVI amyloid fibrils were characterized using X-ray crystallography, circular dichroism (CD) spectroscopy, Fourier transform infrared spectroscopy, NMR spectroscopy, and transmission electron microscopy (TEM).…”

Section: Hiv Infections Continue To Be a Major Health Issuementioning

confidence: 99%

“…SEVI precursors also showed nucleation‐dependent two‐step amyloid formation under several different conditions; however, much still remains to be investigated, for instance, detailed aggregation kinetic analysis and cross‐seeding effects on SEVI amyloid formation. Atomistic and secondary structure and morphology of SEVI amyloid fibrils were characterized using X‐ray crystallography, circular dichroism (CD) spectroscopy, Fourier transform infrared spectroscopy, NMR spectroscopy, and transmission electron microscopy (TEM) .…”

Section: Introductionmentioning

confidence: 99%

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Lee

Ramamoorthy

2018

Protein Science

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Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

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K114 (trans, trans)‐bromo‐2,5‐bis(4‐hydroxystyryl)benzene is an efficient detector of cationic amyloid fibrils

Cited by 7 publications

References 27 publications

Mechanistic Studies of the Inhibition of Insulin Fibril Formation by Rosmarinic Acid

Mechanistic Studies of the Inhibition of Insulin Fibril Formation by Rosmarinic Acid

Axonal and myelinic pathology in 5xFAD Alzheimer’s mouse spinal cord

Semen‐derived amyloidogenic peptides—Key players of HIV infection

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