Insulin Inhibits Aβ42 Aggregation and Prevents Aβ42-Induced Membrane Disruption

Long, Kaho; Williams, Thomas; Urbanc, Brigita

doi:10.1021/acs.biochem.9b00696

Cited by 15 publications

(13 citation statements)

References 36 publications

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“…PICUP was applied to HP36 solution, following the published protocol used for Aβ and insulin. ,, In brief, stock solutions of each 1 mM tris(2,2-bipyridyl)dichlororuthenium(II) hexahydrate (Sigma-Aldrich, St. Louis, MO) and 20 mM ammonium persulfate (APS) (Sigma-Aldrich) were prepared in a 10 mM sodium phosphate buffer. One μL of each stock solution was added to 18 μL of solubilized HP36 solution.…”

Section: Methodsmentioning

confidence: 99%

Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields

2021

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Protein self-assembly plays an important role in cellular processes. Whereas molecular dynamics (MD) represents a powerful tool in studying assembly mechanisms, its predictions depend on the accuracy of underlying force fields, which are known to overly promote protein assembly. We here examine villin headpiece domain, HP36, which remains soluble at concentrations amenable to MD studies. The experimental characterization of soluble HP36 at concentrations of 0.05 to 1 mM reveals concentrationindependent 90% monomeric and 10% dimeric populations. Extensive allatom MD simulations at two protein concentrations, 0.9 and 8.5 mM, probe the HP36 dimer population, stability, and kinetics of dimer formation within two MD force fields, Amber ff14SB and CHARMM36m. MD results demonstrate that whereas CHARMM36m captures experimental HP36 monomer populations at the lower concentration, both force fields overly promote HP36 association at the higher concentration. Moreover, contacts stabilizing HP36 dimers are force-field-dependent. CHARMM36m produces consistently higher HP36 monomer populations, lower association rates, and weaker dependence of these quantities on the protein concentration than Amber ff14SB. Nonetheless, the highest monomer populations and dissociation constants are observed when the TIP3P water model in Amber ff14SB is replaced by TIP4P/2005, showcasing the critical role of the water model in addressing the protein solubility problem in MD.

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Section: Methodsmentioning

confidence: 99%

Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields

2021

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“…Interestingly, it was shown that insulin decreases the quantity of Aβ peptides binding to the cell surface and hence inhibits Aβ aggregation . It was proposed that the inhibition of Aβ aggregation by insulin is due to the binding of insulin to Aβ peptides and Aβ aggregates. , Yet, the specific interactions of insulin with Aβ aggregates are still elusive. The long-term effect of intranasal insulin in AD patients showed that insulin is modifying AD-related pathophysiologic processes and not merely improving symptoms of memory impairment .…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Activity of Insulin on Aβ Aggregation Is Restricted Due to Binding Selectivity and Specificity to Polymorphic Aβ States

Baram

Miller

2020

ACS Chem. Neurosci.

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Clinical trials of intranasal insulin treatment for Alzheimer’s patients have shown cognitive and memory improvement, but the effect of insulin has shown a limitation. It was suggested that insulin molecule binds to Aβ aggregates and impedes Aβ aggregation. Yet, the specific interactions between insulin molecule and Aβ aggregates at atomic resolution are still elusive. Three main conclusions are observed in this work. First, insulin can interact across the fibril only to “U-shape” Aβ fibrils and not to “S-shape” Aβ fibrils. Therefore, insulin is not expected to influence the “S-shape” Aβ fibrils. Second, insulin disrupts β-strands along Aβ fibril-like oligomers via interaction with chain A, which is not a part of the recognition motif. It is suggested that insulin affects as an inhibitor of Aβ fibrillation, but it is limited due to the specificity of the polymorphic Aβ fibril-like oligomer. Third, the current work proposes that insulin promotes Aβ aggregation, when interacting along the fibril axis of Aβ fibril-like oligomer. The coaggregation could be initiated via the recognition motif. The lack of the interactions of insulin in the recognition motif impede the coaggregation of insulin and Aβ. The current work reports the specific binding domains between insulin molecule and polymorphic Aβ fibril-like oligomers. This research provides insights into the molecular mechanisms of the functional activity of insulin on Aβ aggregation that strongly depends on the particular polymorphic Aβ aggregates.

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“…Previous studies have demonstrated the interactions between insulin and Ab. Insulin can inhibit Ab aggregation, enhance Ab degradation, and prevent Ab-induced cellular events, such as membrane disruption and tau phosphorylation (Yamamoto et al, 2018;Long et al, 2019). On the other hand, Ab has also been found to modulate insulin signaling.…”

Section: Discussionmentioning

confidence: 99%

Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation

Zou

Feng

et al. 2020

Front. Pharmacol.

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Neuronal insulin resistance is implicated in neurodegenerative diseases. Icariin has been reported to improve insulin resistance in skeletal muscle cells and to restore impaired hypothalamic insulin signaling in the rats with chronic unpredictable mild stress. In addition, icariin can exert the neuroprotective effects in the mouse models of neurodegenerative diseases. However, the molecular mechanisms by which icariin affects neuronal insulin resistance are poorly understood. In the present study, amyloid-b (Ab) was used to induce insulin resistance in human neuroblastoma SK-N-MC cells. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt T308 phosphorylation and glucose uptake. We found that the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mediated Ab-induced insulin resistance. Icariin treatment markedly reduced Ab-enhanced PTEN protein levels, leading to an improvement in Abinduced insulin resistance. Accordingly, PTEN overexpression obviously abolished the protective effects of icariin on Ab-induced insulin resistance. Furthermore, icariin activated proteasome activity. The proteasome inhibitor MG132 attenuated the effects of icariin on PTEN protein levels. Taken together, these results suggest that icariin protects SK-N-MC cells against Ab-induced insulin resistance by activating the proteasome-dependent degradation of PTEN. These findings provide an experimental background for the identification of novel molecular targets of icariin, which may help in the development of alternative therapeutic approaches for neurodegenerative diseases.

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Insulin Inhibits Aβ42 Aggregation and Prevents Aβ42-Induced Membrane Disruption

Cited by 15 publications

References 36 publications

Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields

Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields

Inhibitory Activity of Insulin on Aβ Aggregation Is Restricted Due to Binding Selectivity and Specificity to Polymorphic Aβ States

Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation

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