Differential Effects of Polyphenols on Insulin Proteolysis by the Insulin-Degrading Enzyme

Zheng, Qingyuan; Kebede, Micheal T.; Lee, Bethany; Krasinski, Claire A.; Islam, Saadman; Wurfl, Liliana A; Kemeh, Merc M.; Ivancic, Valerie A.; Jakobsche, Charles E.; Spratt, Donald E.; Lazo, Noel D.

doi:10.3390/antiox10091342

Cited by 5 publications

(10 citation statements)

References 41 publications

(56 reference statements)

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“…34−37 The basic premise of this approach is simple: the α-helical dichroic spectrum of insulin is sensitive to the extent of proteolytic degradation by IDE. As noted elsewhere, 34,36,37 the magnitude of insulin's ellipticity at 222 nm (i.e., ([θ obs(222 nm) ]) decreases as digestion proceeds. As such, the initial velocity (V 0 ) of insulin proteolysis can be determined from [θ obs(222 nm) ] recorded within the first few minutes of the proteolysis, as previously described.…”

Section: ■ Results and Discussionmentioning

confidence: 69%

“…The Michaelis–Menten kinetic constants for the IDE-dependent degradation of insulin in the absence and presence of Aβ(1–40) or Aβ(pyroE3–42) can be determined using CD spectroscopy. − The basic premise of this approach is simple: the α-helical dichroic spectrum of insulin is sensitive to the extent of proteolytic degradation by IDE. As noted elsewhere, ,, the magnitude of insulin’s ellipticity at 222 nm (i.e., ([θ obs (222 nm) ]) decreases as digestion proceeds.…”

Section: Resultsmentioning

confidence: 99%

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Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides

Kemeh

Lazo

2023

ACS Chem. Neurosci.

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The insulin-degrading enzyme (IDE) is an evolutionarily conserved protease implicated in the degradation of insulin and amyloidogenic peptides. Most of the biochemical and biophysical characterization of IDE's catalytic activity has been conducted using solutions containing a single substrate, i.e., insulin or Aβ(1−40). IDE's activity toward a particular substrate, however, is likely to be influenced by the presence of other substrates. Here, we show by a kinetic assay based on insulin's helical circular dichroic signal and MALDI TOF mass spectrometry that Aβ peptides modulate IDE's activity toward insulin in opposing ways. Aβ(1−40) enhances IDE-dependent degradation of insulin, whereas Aβ(pyroE3−42), the most pathogenic pyroglutamate-modified Aβ peptide in AD, inhibits IDE's activity. Intriguingly, Aβ(pyroE3−42) also inhibits IDE's ability to degrade Aβ(1−40). Together, our results implicate Aβ peptides in the abnormal catabolism of IDE's key substrates.

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Section: ■ Results and Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides

Kemeh

Lazo

2023

ACS Chem. Neurosci.

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“…Decreased peripheral and cerebrospinal fluid IGF-1 levels may be a potential marker of cognitive decline and progression in AD ( 66 ). Insulin-degrading enzyme (IDE) has a great ability to degrade insulin and Aβ42 ( 67 ). IDE acts as an important regulator of Aβ clearance and diabetes, which is associated with neurodegeneration in AD ( 68 ).…”

Section: Manuscript Formattingmentioning

confidence: 99%

Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment

et al. 2022

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The incidence of sporadic Alzheimer’s disease (AD) is increasing in recent years. Studies have shown that in addition to some genetic abnormalities, the majority of AD patients has a history of long-term exposure to risk factors. Neuroendocrine related risk factors have been proved to be strongly associated with AD. Long-term hormone disorder can have a direct detrimental effect on the brain by producing an AD-like pathology and result in cognitive decline by impairing neuronal metabolism, plasticity and survival. Traditional Chinese Medicine(TCM) may regulate the complex process of endocrine disorders, and improve metabolic abnormalities, as well as the resulting neuroinflammation and oxidative damage through a variety of pathways. TCM has unique therapeutic advantages in treating early intervention of AD-related neuroendocrine disorders and preventing cognitive decline. This paper reviewed the relationship between neuroendocrine and AD as well as the related TCM treatment and its mechanism. The advantages of TCM intervention on endocrine disorders and some pending problems was also discussed, and new insights for TCM treatment of dementia in the future was provided.

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“… 16 Kurochkin et al showed that allosteric mutagenesis can be an attractive strategy for increasing the activity of IDE toward Aβ. 18 More recently, we showed that resveratrol sustains IDE’s activity toward Aβ42 19 but has no effect on the enzyme’s ability to degrade insulin, 20 suggesting that resveratrol is a substrate-selective activator of IDE. In spite of the structural and mechanistic advances discussed above, however, outstanding challenges remain in current efforts to develop IDE-centric therapeutics for T2D and AD.…”

Section: Introductionmentioning

confidence: 99%

Exchange Broadening Underlies the Enhancement of IDE-Dependent Degradation of Insulin by Anionic Membranes

et al. 2022

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Insulin-degrading enzyme (IDE) is an evolutionarily conserved ubiquitous zinc metalloprotease implicated in the efficient degradation of insulin monomer. However, IDE also degrades monomers of amyloidogenic peptides associated with disease, complicating the development of IDE inhibitors. In this work, we investigated the effects of the lipid composition of membranes on the IDE-dependent degradation of insulin. Kinetic analysis based on chromatography and insulin’s helical circular dichroic signal showed that the presence of anionic lipids in membranes enhances IDE’s activity toward insulin. Using NMR spectroscopy, we discovered that exchange broadening underlies the enhancement of IDE’s activity. These findings, together with the adverse effects of anionic membranes in the self-assembly of IDE’s amyloidogenic substrates, suggest that the lipid composition of membranes is a key determinant of IDE’s ability to balance the levels of its physiologically and pathologically relevant substrates and achieve proteostasis.

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Differential Effects of Polyphenols on Insulin Proteolysis by the Insulin-Degrading Enzyme

Cited by 5 publications

References 41 publications

Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides

Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides

Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment

Exchange Broadening Underlies the Enhancement of IDE-Dependent Degradation of Insulin by Anionic Membranes

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