Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele

Cook, David G.; Leverenz, James B.; McMillan, Pamela J.; Kulstad, J. Jacob; Ericksen, Sasha; Roth, Richard A.; Schellenberg, Gerard D.; Jin, Lee Way; Kovacina, Kristina S.; Craft, Suzanne

doi:10.1016/s0002-9440(10)63822-9

Cited by 312 publications

(223 citation statements)

References 39 publications

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“…3C,D). This is consistent with the results of Cook et al (2003) which found that IDE levels are reduced by up to 50% in ApoE4ϩ human subjects compared with ApoE4Ϫ subjects.…”

Section: Correlation Of Pi3 Kinase (P85) and Ide In Human Brainssupporting

confidence: 93%

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.

297

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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“…3C,D). This is consistent with the results of Cook et al (2003) which found that IDE levels are reduced by up to 50% in ApoE4ϩ human subjects compared with ApoE4Ϫ subjects.…”

Section: Correlation Of Pi3 Kinase (P85) and Ide In Human Brainssupporting

confidence: 93%

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.

297

188

View full text Add to dashboard Cite

show abstract

“…A recent neuroimaging study indicates that Aβ levels are associated with cognitive impairment in non-demented individuals [35]. Furthermore, Alzheimer's disease patients with an APOE ε4 allele exhibit lower levels of IDE in the hippocampus than those without an APOE ε4 allele [36]. It has been suggested that increased Aβ deposition may result both from the decreased expression of IDE in individuals with an APOE ε4 allele and the decreased IDE levels caused by increased use of IDE for insulin regulation in individuals with diabetes, thus leading to higher levels of Alzheimer's disease pathology in participants with both diabetes and APOE [18].…”

Section: Discussionmentioning

confidence: 99%

Presence of the APOE ε4 allele modifies the relationship between type 2 diabetes and cognitive performance: the Maine–Syracuse Study

et al. 2009

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Aims/hypothesis The primary aim of this study was to determine whether the presence of one or more APOE ε4 alleles modifies the association between diabetes (defined by glucose ≥7 mmol/l or treatment) and cognitive function. Methods Diabetic status and APOE genotype interactions were assessed cross-sectionally for 826 communitydwelling, stroke-free, non-demented individuals (526 nondiabetic non-APOE ε4 carriers, 174 non-diabetic APOE ε4 carriers, 87 diabetic APOE ε4 non-carriers, 39 diabetic APOE ε4 carriers) ranging in age from 50 to 98 years. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the similarities subtest from the Wechsler Adult Intelligence Scale, and four composite scores derived from 17 additional neuropsychological tests. Multiple linear regression analyses were employed to relate diabetes and APOE genotype to cognitive performance and to examine the interaction between these two risk factors as they relate to cognitive performance. Multiple cardiovascular disease risk factors were statistically controlled. Results With adjustment for age, education, sex, race/ ethnicity and APOE genotype, performance level was lower for the diabetic than for the non-diabetic group for the MMSE, the similarities subtest and each of the cognitive composites with the exception of the verbal memory composite. Interactions (p<0.05) between diabetes and APOE genotype were found for all but the visual-spatial memory/organisation composite. The negative association between diabetes and cognitive performance was of a higher magnitude for individuals who carry one or more APOE ε4 alleles. Results were similar with additional adjustment for cardiovascular disease and associated risk factors. Conclusions/interpretation The presence of one or more APOE ε4 alleles modifies the association between diabetes and cognitive function.

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“…185,186 There are many lines of evidence suggesting IDE dysfunction in AD pathogenesis. For example, levels of IDE are reduced in AD, 187,188 and AD patients may display impaired insulin clearance. 189 Diabetes mellitus is also associated with increased risk for AD, 190,191 IDE haplotypes have an association with plasma Ab1-42 levels, 192 and other metabolic imbalances characteristic of hyperinsulinaemia may impair IDE activity.…”

Section: Ab-degrading Enzymesmentioning

confidence: 99%

“…Furthermore, apoE isoforms may have a modulatory role in IDE expression as APOEe4 carrying AD patients have reduced levels of IDE in the hippocampus and cortex when compared to non-APOEe4 carrying AD patients and controls. 188 Thus, improving IDE metabolism of Ab is of possible therapeutic benefit. Given the parallel decrease in IDE and insulin levels in AD patients, it is possible that insulin may regulate IDE expression.…”

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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Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele

Cited by 312 publications

References 39 publications

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

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

Presence of the APOE ε4 allele modifies the relationship between type 2 diabetes and cognitive performance: the Maine–Syracuse Study

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

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