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PubMed2006

Weak independent association signals between IDE polymorphisms, Alzheimer's disease and cognitive measures.

Functional and genetic studies suggest that insulin-degrading enzyme (IDE) may be a strong functional and positional candidate. As there is a lack of consensus in regards to the level and location of IDE association signals we aimed to clarify these discrepancies through genotyping 28 SNPs in a large case-control collective together with quantitative measures of cognitive ability (MMSE). Four SNPs (rs11187007, rs2149632_ide12, rs11187033, rs11187040) were found to be associated with AD (nominal p<0.01). Tests with MMSE scores adjusted for disease duration identified associations, with the most significant result for rs1999763 (nominal p=0.008). Similarly, different reconstructed IDE haplotypes were associated with AD and higher MMSE scores. The association signals are only borderline significant after adjustment for multiple testing, but add further evidence to previous published results on the association between IDE and AD or MMSE. A subgroup analysis indicated more prominent associations with AD in younger, and with MMSE in older patients. There may be two independent effects mediated by IDE variants, risk for AD and modification of disease progression.

Aged↗
PubMed2006

Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease.

In this study we report that the membrane-bound, but not cytosolic insulin degrading enzyme (IDE) protein concentration and IDE activity are significantly decreased in the hippocampal formation of cases affected by mild cognitive impairment (MCI) which are at high risk to develop Alzheimer's disease (AD), relative to normal neurological controls. Membrane-bound IDE protein concentrations and activity in the hippocampal formation continued to decrease during the conversion from MCI to mild-severe AD. This selective decrease in hippocampal membrane-bound, but not cytosolic, IDE concentration and activity was tissue specific since no changes in either membrane-bound or cytosolic IDE were found in the occipital cortex of the same cases examined. Most interestingly, the decreased hippocampal membrane-bound IDE protein activity negatively correlated with brain beta-amyloid (Abeta)X-42 content in MCI and in AD brain. The study tentatively suggests that interventions aimed at promoting membrane-bound IDE activities in the brain of MCI cases may help to prevent the onset and possibly the progression into AD through mechanisms involving the clearance of monomeric Abeta from the brain.

Aged↗
PubMed2006

Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE.

Insulin degrading enzyme (IDE) is one of the principal proteases involved in the degradation of the beta-amyloid peptide, which is the major constituent of senile plaques in Alzheimer's disease (AD) brains. Previous association studies between AD and IDE have produced inconsistent results which may be indicative of a need for larger case-control series to identify what may be a relatively small effect size. Thus, we performed a large association study using four SNPs in the 276-kb haplotype block in and around IDE (IDE_7, IDE_9, IDE_14 and HHEX_23) in a previously unpublished Swedish and a UK case-control series, and combined our data with a previously reported Swedish case-control sample set from Prince et al., 2003. The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE_9 located in the 3'-end of the IDE gene after conservative multiple testing Bonferroni correction (p=0.005). The effect seemed to predominate in male cases. However, we did not observe a globally significant association to haplotypes generated from three "tag" SNPs. These findings indicate a role for IDE in AD, and provide models that may improve chances of further independent replication.

Aged↗
PubMed2004

Clearance of Alzheimer's Abeta peptide: the many roads to perdition.

The amyloid hypothesis of Alzheimer's disease (AD) maintains that the accumulation of the amyloid beta protein (Abeta) is a critical event in disease pathogenesis. A great deal of both academic and commercial research has focused on the mechanisms by which Abeta is generated. However, investigations into the mechanisms underlying Abeta clearance have blossomed over the last several years. This minireview will summarize pathways involved in the removal of cerebral Abeta, including enzymatic degradation and receptor-mediated efflux out of the brain.

Alzheimer Disease↗
PubMed2004

Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein.

The causes of cerebral accumulation of amyloid beta-protein (Abeta) in most cases of Alzheimer's disease (AD) remain unknown. We recently found that homozygous deletion of the insulin-degrading enzyme (IDE) gene in mice results in an early and marked elevation of cerebral Abeta. Both genetic linkage and allelic association in the IDE region of chromosome 10 have been reported in families with late-onset AD. For IDE to remain a valid candidate gene for late-onset AD on functional grounds, it must be shown that partial loss of function of IDE can still alter Abeta degradation, but without causing early, severe elevation of brain Abeta. Here, we show that naturally occurring IDE missense mutations in a well-characterized rat model of type 2 diabetes mellitus (DM2) result in decreased catalytic efficiency and a significant approximately 15 to 30% deficit in the degradation of both insulin and Abeta. Endogenously secreted Abeta(40) and Abeta(42) are significantly elevated in primary neuronal cultures from animals with the IDE mutations, but there is no increase in steady-state levels of rodent Abeta in the brain up to age 14 months. We conclude that naturally occurring, partial loss-of-function mutations in IDE sufficient to cause DM2 also impair neuronal regulation of Abeta levels, but the brain can apparently compensate for the partial deficit during the life span of the rat. Our findings have relevance for the emerging genetic evidence suggesting that IDE may be a late-onset AD-risk gene, and for the epidemiological relationships among hyperinsulinemia, DM2, and AD.

Alzheimer Disease↗
PubMed2003

Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele.

Abeta is the major component of amyloid plaques characterizing Alzheimer's disease (AD). Abeta accumulation can be affected by numerous factors including increased rates of production and/or impaired clearance. Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain. We have previously shown that AD patients exhibit abnormalities in insulin metabolism that are associated with apoliprotein E (APOE) status. The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD. We report that hippocampal IDE protein is reduced by approximately 50% in epsilon4+ AD patients compared to epsilon4- patients and controls. The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status. Hippocampal IDE mRNA levels were also reduced in AD patients with the epsilon4 allele compared to AD and normal subjects without the epsilon4 allele. These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Abeta metabolism.

Aged↗
PubMed1988

Cellular localization of insulin-degrading enzyme in rat liver using monoclonal antibodies specific for this enzyme.

Although insulin-degrading enzyme (IDE) has been implicated in the intracellular degradation of insulin, the cellular localization of this enzyme is still controversial. In the present study, we have examined the cellular localization of IDE in the rat liver by three different techniques using monoclonal antibodies. First, direct immunohistochemical staining of rat liver with one of the monoclonal antibodies revealed that IDE immunoreactivity mainly exists in parenchymal cells, especially in the vicinity of the portal tract and also in the epithelium of the bile duct under light microscopy. In the electron microscopic study, IDE immunoreactivity was found in the cytoplasm near the rough endoplasmic reticulum but not in the plasma membrane, nucleus, or mitochondria. Second, immunoblotting analysis of the subcellular fraction in rat liver showed that the monoclonal antibody specifically reacted with a single polypeptide in the cytosolic fraction, of apparent Mr 110,000, which was consistent with the Mr of IDE. However, a polypeptide band corresponding to IDE could not be observed in the plasma membrane, mitochondrial, or lysosomal fraction. Third, IDE was only detectable in the cytosolic fraction by sandwich radioimmunoassay using two monoclonal antibodies. These results all suggest that IDE is a cytosolic enzyme.

Animals↗
PubMed2001

Development of a bloodspot assay for insulin.

BACKGROUND: Bloodspot assays for hormones have advantages of ease of collection/transportation, minimal invasiveness and small blood volume. Such an approach would be of use in epidemiological studies of insulin resistance in children and neonates. METHODS: A two-site chemiluminescent immunoassay for the quantitation of insulin in bloodspots dried on filter paper, based on modifications of a commercially available kit, was used. Analysis was carried out on two 3-mm diameter discs punched out from whole blood standards and test samples. RESULTS: The detection limit of the assay was 5.9 pmol/l of whole blood, with mean intra-assay CV and mean inter-assay CV being <15% above 24 pmol/l. The mean recovery of added insulin was 83%. Comparison of paired whole bloodspots and serum samples collected simultaneously gave a correlation of 0.89. The bloodspot insulin concentrations were stable in excess of 2 months when stored at -20 degrees C and were not susceptible to degradation after four freeze-thaw cycles. CONCLUSIONS: This simple and convenient method is suitable for the measurement of insulin in small volumes of blood collected on filter paper cards and can be applied to epidemiological studies of insulin resistance.

Adult↗
PubMed1998

Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme.

Insulin-degrading enzyme (IDE) is an evolutionarily conserved neutral thiol metalloprotease expressed in all mammalian tissues whose biological role is not well established. IDE has highly selective substrate specificity. It degrades insulin, glucagon, atrial natriuretic peptide, transforming growth factor alpha but does not act on related hormones and growth factors. The structural properties determining whether a peptide is an IDE substrate are essentially unknown. The reported cleavage sites are not consistent with simple peptide-bond recognition and it was proposed that IDE recognizes in its substrates some elements of tertiary structure. We noticed that although IDE substrates are functionally unrelated, the majority of them share a specific property, an ability to form under certain conditions amyloid fibrils. Utilizing the residue pattern recognition procedure, this study reveals a common motif in the sequences of IDE substrates, HNHHHPSH, where H is wholly or partly hydrophobic character, N is small and neutral, P is polar, and S is polar and/or small amino acid residue. It is proposed that this sequence motif predetermines a structure recognized by IDE. The identified motif appears to be essentially the same as the proposed earlier consensus sequence for amyloid-forming peptides [Turnell and Finch, J. Mol. Biol. 227 (1992) 1205-1223]. The study suggests that IDE may play a role in elimination of potentially toxic amyloidogenic peptides.

Amino Acid Sequence↗
PubMed1999

Differences in the cellular processing of AspB10 human insulin compared with human insulin and LysB28ProB29 human insulin.

Cellular metabolism studies were performed comparing human insulin with two rapid-acting analogs, LysB28ProB29 insulin (LysPro) and AspB10 insulin (B10-Asp). B10-Asp bound to isolated hepatocytes at 37 degrees C to a greater extent than LysPro or native insulin, which were equivalent. The rate of degradation was similar for the three materials, resulting in a significant reduction in the degraded/bound ratio for the B10 analog. The processing of membrane-bound material was examined by incubating cells with hormone at 4 degrees C, removing unbound insulin, and incubating the cells at 37 degrees C. Again, binding was greater for B10-Asp versus LysPro or native insulin, with a reduction in the degraded/bound ratio. Hormone internalization and processing was examined by an acid wash of cells incubated with 125I(A14)-labeled hormone to remove surface-bound materials. The processing rate was slower for B10-Asp versus LysPro or native insulin. Cell extraction and examination on molecular-sieve chromatography confirmed that B10-Asp was processed at a slower rate than either LysPro or native insulin. Intact B10-Asp was found in the cell after 4 hours, whereas all native insulin and LysPro were degraded by 90 to 120 minutes. B10-Asp also caused a greater incorporation of thymidine into DNA in cultured cells than LysPro or native insulin, which were similar. These data show that the cellular processing of LysPro is essentially identical to that of native insulin. However, B10-Asp has markedly different properties and is processed much more slowly. The prolonged cell residence time of B10-Asp could contribute to its greater effects on cell growth and mitogenesis.

Animals↗
PubMed1987

Proteolytic degradation of insulin and glucagon in rat brain during ontogenesis.

The degradation of insulin and glucagon was investigated in rat brain, kidney, and liver during postnatal ontogenesis. It was found that a maximal activity around 13 d is unique for CNS and differs remarkably from time-course in liver and kidney. It is concluded that this result supports the hypothesis of a growth promoting role of insulin in developing rat brain.

Aging↗
PubMed1997

Identification of the cleavage sites of transforming growth factor alpha by insulin-degrading enzymes.

Insulin-degrading enzyme (IDE) is a sulfhydryl-dependent metalloproteinase with a zinc binding site unique to a new class of proteinases. The enzyme is relatively specific for a number of hormones/growth factors, such as insulin, atrial natriuretic peptide, IGF-II, and proinsulin. In this study we have identified the amino-acid bonds cleaved by IDE in transforming growth factor-alpha. High-performance liquid chromatography was used to separate the peptides generated by the degradation of 125I-TGF-alpha. The peptides were then submitted to sequential Edman degradation to determine the peptide bond broken. Cleavage sites were found at amino acids, 10-11 (Asp-Ser), 25-26 (Val-Gln), 28-29 (Asp-Lys), and 30-31 (Pro-Ala). In agreement with studies of cleavage sites of other hormones by this enzyme, no clear amino-acid specificity was seen. However, examination of the sites on a three-dimensional model of TGF-alpha suggest the primary mechanism used by IDE for determining cleavage sites is the tertiary structure of the substrate.

Animals↗
PubMedDate not supplied

Metabolism of a mutant insulin by a receptor-mediated process and an insulin degrading enzyme.

The metabolism of a mutant insulin, [LeuB25]-insulin, was studied in vitro and in vivo. Porcine or mutant insulin (4 micrograms/kg body weight) was injected i.v. into streptozotocin-induced diabetic rats and their plasma glucose and insulin levels were determined. The half-lives of porcine and mutant insulin were 3 min and 18 min, respectively. The ability of the mutant insulin to lower the blood glucose levels was 38% of that of normal when the glucose levels at the nadir were compared. Receptor-mediated degradation of the mutant insulin assessed by chromatography of the degraded materials in the media after incubation with cells was less compared with that of porcine insulin (4% vs. 24%). The media containing the insulin degrading enzyme (IDE) of IM-9 cells and rat livers degraded porcine and mutant insulin to the same extent. These results suggest that the decreased clearance of insulin is due to the decreased receptor binding and the decreased receptor-mediated degradation, but is not due to the decreased degradation by IDE.

Animals↗
PubMed2003

Non-covalent interaction of ubiquitin with insulin-degrading enzyme.

Insulin-degrading enzyme (IDE) is a metalloprotease implicated in insulin degradation and suggested to have a variety of additional functions, including the clearance of amyloid beta peptides of Alzheimer's disease. Little is known about endogenous proteins that may interact with and modulate IDE's activity in the cell. We purified and characterized two proteins from mouse leukemic splenocytes that interact with IDE and inhibit its insulin-degrading activity. A protein of 14 kDa was similar to a competitive IDE inhibitor reported previously. The major inhibitor was identified by amino acid sequencing as ubiquitin, a protein that is post-translationally covalently attached to other intracellular proteins and regulates diverse cellular processes. Ubiquitin inhibited insulin-degrading activity of IDE and diminished crosslinking of 125I-insulin to IDE in a specific, concentration-dependent, reversible, and ATP-independent manner. Ubiquitin did not affect the crosslinking of 125I-insulin to insulin receptors or of 125I-atrial natriuretic peptide (ANP) to its receptor guanylate cyclase-A. These findings suggest a novel role for ubiquitin or perhaps proteins with ubiquitin-like domains in regulating the function of IDE.

Animals↗
PubMed2002

Polymorphisms of insulin degrading enzyme gene are not associated with Alzheimer's disease.

To date, allele 4 of the apolipoprotein E gene is the only risk factor that has been robustly associated with Alzheimer's disease (AD). Identification and molecular characterization of other risk factors is of great interest. The insulin degrading enzyme (IDE) is an attractive candidate gene since: (i), previous studies have identified a possible role that IDE plays in the degradation and clearance of human amyloid beta from migroglial cells and neurons; and (ii), this gene is located on chromosome 10q23-q24, a region in which a susceptibility locus for AD has recently been mapped. In the present study, we have assessed whether IDE is a potential risk factor for AD. Two intronic single nucleotide polymorphisms (SNPs) were genotyped in a case-control study including 388 French individuals. No association between these SNPs and AD was detected.

Aged↗
PubMed2003

Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE).

Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values < or =0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted.

Aged↗
PubMed1999

Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques.

The anatomical distribution of insulin-degrading enzyme (IDE) was studied in normal and Alzheimer's disease (AD) human brains. By use of a monospecific, polyclonal antiserum against the enzyme we identified IDE antigen in multiple cortical and subcortical neurons. Glia did not show IDE immunoreactivity. In AD brains immunostaining appeared stronger than in controls and appeared not only in neurons but also in senile plaques. In a probable case of Lewy body variant of AD Lewy bodies in neurons of the Nuc. basalis of Meynert were immunopositive for IDE. Our anatomical data suggest that the enzyme is associated with typical neuropathologic hallmarks of AD and its expression appears up-regulated in some brain areas.

Adult↗