Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid β-Protein

Farris, Wesley; Mansourian, Stefan; Leissring, Malcolm A.; Eckman, Elizabeth A.; Bertram, Lars; Eckman, Christopher B.; Tanzi, Rudolph E.; Selkoe, Dennis J.

doi:10.1016/s0002-9440(10)63229-4

Cited by 237 publications

(164 citation statements)

References 66 publications

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“…This enzyme, a metalloprotease enzyme responsible for insulin degradation, had been shown to have a key role in b-amyloid (Ab) peptide degradation both in vitro and in vivo, and was selective for Ab monomer. [9][10][11] Thus, substances which induce the upregulation of IDE enzyme are expected to be promising drugs for the treatment of Alzheimer's disease. Compound 1 induced reporter gene expression under the control of the IDE promoter more than three times at a concentration of 100 mM.…”

Section: Biological Activitymentioning

confidence: 99%

Isolation and structure elucidation of tumescenamides A and B, two peptides produced by Streptomyces tumescens YM23-260

et al. 2010

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Two peptides, tumescenamides A and B, were isolated from the fermentation broth of a marine bacterium, Streptomyces tumescens YM23-260. The structure of tumescenamide A was determined to be a cyclic depsipeptide consisting of a-amino-2-butenoic acid, tyrosine, valine, leucine and threonine, substituted with a 2,4-dimethylheptanoyl residue at the a-NH 2 position. INTRODUCTIONTerpenoids are the largest family of compounds found in nature with over 24 000 known examples and are mainly produced by fungi and plants. Production of these compounds by actinomycetes including Streptomyces, however, was rather rare, and only limited numbers of compounds were reported to date. 1 In view of the excellent ability of Streptomyces to produce many kinds of bioactive secondary metabolites with structural diversity, this phenomenon seemed to be interesting for us.Being stimulated in this phenomenon, we started screening for terpenoids produced by actinomycetes and succeeded in the isolation of oxaloterpins 2 and napyradiomycin analogs. 3 Our strategy for screening of terpenoids in these cases was as follows: (1) To carry out more efficient screening of terpenoids, we started using liquid chromatography NMR (LC-NMR) that enabled to detect

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Section: Biological Activitymentioning

confidence: 99%

Isolation and structure elucidation of tumescenamides A and B, two peptides produced by Streptomyces tumescens YM23-260

et al. 2010

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“…Loss-offunction mutations or pharmacological inhibition of IDE increases amyloid accumulation in pancreatic beta cells and in the central nervous system [19][20][21]. On the other hand, IDE overproduction increases insulin degradation and decreases the efficiency of insulin stimulation in the insulin signalling pathway [22].…”

Section: Introductionmentioning

confidence: 99%

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

et al. 2009

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Aims/hypothesis Hepatic insulin degradation decreases in type 2 diabetes. Insulin-degrading enzyme (IDE) plays a key role in insulin degradation and its gene is located in a diabetes-associated chromosomal region. We hypothesised that IDE may be regulated by insulin and/or glucose in a liver cell model. To validate the observed regulation of IDE in vivo, we analysed biopsies of human adipose tissue during different clamp experiments in men. Methods Human hepatoma HepG2 cells were incubated in normal (1 g/l) or high (4.5 g/l) glucose medium and treated with insulin for 24 h. Catalytic activity, mRNA and protein levels of IDE were assessed. IDE mRNA levels were measured in biopsies of human subcutaneous adipose tissue before and at 240 min of hyperinsulinaemic, euglycaemic and hyperglycaemic clamps. Results In HepG2 cells, insulin increased IDE activity under normal glucose conditions with no change in IDE mRNA or protein levels. Under conditions of high glucose, insulin increased mRNA levels of IDE without changes in IDE activity. Both in normal and high glucose medium, insulin increased levels of the catalytically more active 15a IDE isoform compared with the 15b isoform. In subcutaneous adipose tissue, IDE mRNA levels were not significantly upregulated after euglycaemic or hyperglycaemic clamps. Conclusions/interpretation Insulin increases IDE activity in HepG2 cells in normal but not in high glucose conditions. This disturbance cannot be explained by corresponding alterations in IDE protein levels or IDE splicing. The loss of insulin-induced regulation of IDE activity under hyperglycaemia may contribute to the reduced insulin extraction and peripheral hyperinsulinaemia in type 2 diabetes.

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“…Insulin-degrading enzyme (IDE), a metalloprotease enzyme responsible for insulin degradation, has been demonstrated to play a key role in ␤-amyloid (A␤) peptide degradation both in vitro and in vivo and is selective for A␤ monomer Farris et al, 2003Farris et al, , 2004. Genetic linkage studies have linked Alzheimer's disease (AD) and plasma A␤42 levels to chromosome 10q, which harbors the IDE gene (Bertram et al, 2000;ErtekinTaner et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention

Zhao¹,

Teter²,

Morita³

et al. 2004

J. Neurosci.

289

188

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Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading ␤-amyloid (A␤) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce A␤. Little is known, however, about the cellular and molecular regulation of IDE protein. Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by ϳ25%. Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a causeeffect relationship between insulin signaling and IDE upregulation. Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. Consistent with IDE function in the degradation of A␤ monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased A␤ monomer levels. These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD.

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Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid β-Protein

Cited by 237 publications

References 66 publications

Isolation and structure elucidation of tumescenamides A and B, two peptides produced by Streptomyces tumescens YM23-260

Isolation and structure elucidation of tumescenamides A and B, two peptides produced by Streptomyces tumescens YM23-260

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention

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