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

Bernstein, Hans‐Gert; Ansorge, Siegfried; Riederer, Peter; Reiser, Michael; Frölich, Lutz; Bogerts, Bernhard

doi:10.1016/s0304-3940(99)00135-4

Cited by 95 publications

(81 citation statements)

References 16 publications

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“…S2). Although a definite proof will require direct biochemical characterization after a large scale purification, these results suggest that IDE⅐A␤SCx exists in vivo in normal rodent brain and remains associated with amyloid deposits in senile plaques, in accordance with the reported immunohistochemical findings of IDE in AD brains (28).…”

Section: Ide and A␤ Form A Complex That Resists Dissociation Withsupporting

confidence: 87%

“…Several proteins have been shown to interact with A␤ in a manner that is resistant to SDS, including apolipoprotein E isoforms, apolipoprotein J, ␣2-macroglobulin (␣2M), transthyretin, gelsolin, and the ␣7-nicotinic acetylcholine receptor subunit (33)(34)(35)(36)(37)(38). Some of these proteins, like IDE, have been found in close association with or within amyloid plaques in AD brains (28). 4 The best studied binding requirements were those of the apolipoprotein E⅐A␤ complex, showing that the N-terminal region of A␤ His 13 -Lys 16 may interact with the C terminus of the peptide for the strong binding to a natively folded apolipoprotein E (34).…”

Section: Discussionmentioning

confidence: 99%

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The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide

Llovera

Tullio

Alonso

et al. 2008

Journal of Biological Chemistry

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Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid ␤ (A␤) in the mammalian brain.Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with A␤ that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. A␤ sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated A␤ was competent to associate irreversibly with IDE following a very slow kinetics (t1 ⁄ 2 ϳ 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of A␤ takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that A␤ remained bound to a ϳ25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE⅐A␤ complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with A␤. Taken together, these results are suggestive of an unprecedented mechanism of conformationdependent substrate binding that may perturb A␤ clearance, insulin turnover, and promote AD pathogenesis.

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Section: Ide and A␤ Form A Complex That Resists Dissociation Withsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide

Llovera

Tullio

Alonso

et al. 2008

Journal of Biological Chemistry

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“…One of them was identified as ubiquitin, which, upon binding with IDE in a reversible and ATP-independent manner, exhibits a strong inhibitory effect at physiological concentrations. Ubiquitin and IDE are present in both neurofibrillary tangles and senile plaques (35)(36)(37)(38), raising the possibility that ubiquitin may regulate IDE activity in these pathological lesions. Allosteric properties of IDE activity have also been elucidated in which binding of certain peptide substrates to one subunit of IDE induces a conformational change that shifts the equilibrium to the more active dimer while also activating the adjacent subunit (39).…”

Section: Discussionmentioning

confidence: 99%

Decreased Catalytic Activity of the Insulin-degrading Enzyme in Chromosome 10-Linked Alzheimer Disease Families

Kim

Hersh

Leissring

et al. 2007

Journal of Biological Chemistry

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Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades the amyloid ␤-peptide, the key component of Alzheimer disease (AD)-associated senile plaques. We have previously reported evidence for genetic linkage and association of AD on chromosome 10q23-24 in the region harboring the IDE gene. Here we have presented the first functional assessment of IDE in AD families showing the strongest evidence of the genetic linkage. We have examined the catalytic activity and expression of IDE in lymphoblast samples from 12 affected and unaffected members of three chromosome 10-linked AD pedigrees in the National Institute of Mental Health AD Genetics Initiative family sample. We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families. Further, we have shown the decrease in activity is not due to reduced IDE expression, suggesting the possible defects in IDE function in these AD families. In attempts to find potential mutations in the IDE gene in these families, we have found no coding region substitutions or alterations in splicing of the canonical exons and exon 15b of IDE. We have also found that total IDE mRNA levels are not significantly different in sporadic AD versus age-matched control brains. Collectively, our data suggest that the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression, further supporting a role for IDE in AD pathogenesis.2 is the primary component of senile plaques, a pathological hallmark in the brains of patients with Alzheimer disease (AD). Elevated levels of cerebral A␤ have also been observed in AD patients (1, 2), implicating excessive accumulation of A␤ as a key pathogenic event in AD. Unlike early onset autosomal dominant AD, the vast majority of AD cases do not show any clear evidence of Mendelian transmission and predominantly present with late onset AD (LOAD) (onset age Ͼ65). However, there is evidence that genetic factors play a significant role in modifying the disease risk/age of onset in the majority of LOAD cases (3, 4). To date, only the ⑀4 allele of the apolipoprotein E gene (APOE) has been firmly established as a LOAD genetic risk factor and has been proposed to be involved in A␤ clearance (5). Cerebral A␤ accumulation has been proposed to greatly influence the age of onset of LOAD and is determined by the amount of A␤ generated versus the amount that is degraded and exported from the brain over one's lifetime (6, 7).Several proteases have been identified to degrade A␤, including neprilysin, plasmin, endothelin-converting enzyme-1 as well as insulin-degrading enzyme (IDE) (EC 3.4.24.56) (1). IDE, also called insulysin, is a zinc metalloprotease that cleaves small polypeptides, many of which share amyloid fibril-forming ability, including insulin, atrial naturetic peptide, amylin, calcitonin, and A␤ (8, 9). IDE is a major protease to degrade soluble, monomeric A␤ (10, 11) an...

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“…17,18 By contrast, insulysin immunoreactivity is marked in hippocampal and neocortical neurons. 19,20 Several genetic association studies tested for an association between neprilysin or insulysin gene variants and AD, but gave controversial results. [21][22][23][24][25] To date, the expression of ECE-1 in human brain had never been studied, and its potential role in the pathogenesis of AD had never been assessed.…”

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confidence: 99%

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

et al. 2004

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Cerebral accumulation of b-amyloid peptide (Ab) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate Ab-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to Ab deposition, further suggesting a physiological role in Ab clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR ¼ 0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical Ab clearance and offer new potential targets for therapeutic interventions in AD.

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

Cited by 95 publications

References 16 publications

The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide

The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid β Peptide

Decreased Catalytic Activity of the Insulin-degrading Enzyme in Chromosome 10-Linked Alzheimer Disease Families

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

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