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

Zhao, Lingjuan; Teter, Bruce; Morita, Takashi; Lim, Giselle P.; Ambegaokar, Surendra S.; Ubeda, Oliver J.; Frautschy, Sally A.; Cole, Greg M.

doi:10.1523/jneurosci.2860-04.2004

Cited by 303 publications

(211 citation statements)

References 39 publications

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“…Hence current diabetes therapeutic(s) may have value in treating Alzheimer's disease. Potential molecular connections include abnormal expression/ activity of insulin-degrading enzyme [7,8], glycogen synthase kinase-3 (GSK3) [9,10], cholesterol biosynthesis enzymes [11] and activated glycation end-products [12,13], and cerebrovascular alterations [14]. However the major clinical commonality in epidemiological studies is hyperinsulinaemia (indicative of insulin resistance).…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

et al. 2012

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Aims/hypothesis We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feedingevoked cognitive deficit by improving insulin sensitivity. Methods Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n024), standard chow (SC; n016), HF + metformin (144 mg/kg in diet; n020) or SC + metformin (144 mg/kg in diet; n016) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. Results HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. Conclusions/interpretation Metformin prevented the metabolic but not cognitive alterations associated with HF feeding.The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

et al. 2012

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“…195 Insulin signalling was also shown to modulate IDE levels in vitro, in a transgenic mouse model and in human AD brain samples. 196 As such, enhancing the efficacy of insulin signalling in the brain may in turn increase IDE levels and improve Ab degradation. In addition, this insulin signalling and IDE deficiencies that characterize AD may be incorporated into diagnostic tests, as discussed in a later section.…”

Section: Ab-degrading Enzymesmentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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“…It is possible that the deficit in IDE activity at a high glucose concentration may lead to a compensatory increase in IDE expression. A study carried out in primary hippocampal neuron culture suggested that insulin may induce the increase in IDE protein level through the phosphatidylinositol-3 kinase pathway; however, the glucose concentration in the culture medium was not stated [30].…”

Section: Discussionmentioning

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

Cited by 303 publications

References 39 publications

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

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

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