CoChat
Sign Up
Cited by 15Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Regulatory feedback cycle of the insulin-degrading enzyme and the amyloid precursor protein intracellular domain: implications for Alzheimer’s disease

Open access
Lauer, Anna A., Mett, Janine, Janitschke, Daniel, Thiel, Andrea, Stahlmann, Christoph P., Bachmann, Cornel M., Ritzmann, Felix, Schrul, Bianca +6 more·2020·Aging Cell
DOI 10.1111/acel.13264PMC PMC7681056
Open this paper in CoChat — free accountOpen PDF

Abstract

One of the major pathological hallmarks of Alzheimer´s disease (AD) is an accumulation of amyloid‐β (Aβ) in brain tissue leading to formation of toxic oligomers and senile plaques. Under physiological conditions, a tightly balanced equilibrium between Aβ‐production and ‐degradation is necessary to prevent pathological Aβ‐accumulation. Here, we investigate the molecular mechanism how insulin‐degrading enzyme (IDE), one of the major Aβ‐degrading enzymes, is regulated and how amyloid precursor protein (APP) processing and Aβ‐degradation is linked in a regulatory cycle to achieve this balance. In absence of Aβ‐production caused by APP or Presenilin deficiency, IDE‐mediated Aβ‐degradation was decreased, accompanied by a decreased IDE activity, protein level, and expression. Similar results were obtained in cells only expressing a truncated APP, lacking the APP intracellular domain (AICD) suggesting that AICD promotes IDE expression. In return, APP overexpression mediated an increased IDE expression, comparable results were obtained with cells overexpressing C50, a truncated APP representing AICD. Beside these genetic approaches, also AICD peptide incubation and pharmacological inhibition of the γ‐secretase preventing AICD production regulated IDE expression and promoter activity. By utilizing CRISPR/Cas9 APP and Presenilin knockout SH‐SY5Y cells results were confirmed in a second cell line in addition to mouse embryonic fibroblasts. In vivo, IDE expression was decreased in mouse brains devoid of APP or AICD, which was in line with a significant correlation of APP expression level and IDE expression in human postmortem AD brains. Our results show a tight link between Aβ‐production and Aβ‐degradation forming a regulatory cycle in which AICD promotes Aβ‐degradation via IDE and IDE itself limits its own production by degrading AICD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/acel.13264

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SGK1 may promote expression or activity of ADAM10 and IDE, enhancing APP metabolism through the non-amyloidogenic pathway and increasing Aβ degradation.

    “This finding suggests SGK1 may promote the expression or activity of ADAM10 and IDE, thereby enhancing the metabolism of APP through the non-amyloidogenic β pathway and increasing the degradation of Aβ”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Lauer et al., 2020

    The Abstract and Discussion report that APP intracellular domain (AICD) promotes IDE expression and IDE-mediated Aβ degradation. They do not identify SGK1 or ADAM10 as drivers of those effects. The Introduction also describes non-amyloidogenic APP processing as an α- and γ-secretase pathway, not the β pathway printed in the citing sentence. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 42

  1. Belyaev, N. D., Kellett, K. A., Beckett, C., Makova, N. Z., Revett, T. J., Nalivaeva, N. N., Hooper, N. M., & Turner, A. J. (2010). The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}‐secretase‐dependent pathway. Journal of Biological Chemistry, 285(53), 41443‐ 41454. 10.1074/jbc.M110.141390 20961856 PMC3009870 · DOI
  2. Belyaev, N. D., Nalivaeva, N. N., Makova, N. Z., & Turner, A. J. (2009). Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease. EMBO Reports, 10(1), 94‐ 100. 10.1038/embor.2008.222 19057576 PMC2613207 · DOI
  3. Cao, X., & Sudhof, T. C. (2001). A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science, 293(5527), 115‐ 120. 10.1126/science.1058783 11441186 · DOI · Paper page
  4. Ceglia, I., Reitz, C., Gresack, J., Ahn, J. H., Bustos, V., Bleck, M., Zhang, X., Martin, G., Simon, S. M., Nairn, A. C., Greengard, P., & Kim, Y. (2015). APP intracellular domain‐WAVE1 pathway reduces amyloid‐beta production. Nature Medicine, 21(9), 1054‐ 1059. 10.1038/nm.3924 PMC4560977 26280122 · DOI · Paper page
  5. Chen, G. F., Xu, T. H., Yan, Y., Zhou, Y. R., Jiang, Y., Melcher, K., & Xu, H. E. (2017). Amyloid beta: structure, biology and structure‐based therapeutic development. Acta Pharmacologica Sinica, 38(9), 1205‐ 1235. 10.1038/aps.2017.28 28713158 PMC5589967 · DOI · Paper page
  6. Du, J., Sun, B., Chen, K., Fan, L., & Wang, Z. (2009). Antagonist of peroxisome proliferator‐activated receptor gamma induces cerebellar amyloid‐beta levels and motor dysfunction in APP/PS1 transgenic mice. Biochemical and Biophysical Research Communications, 384(3), 357‐ 361. 10.1016/j.bbrc.2009.04.148 19422805 · DOI · Paper page
  7. Du, J., Zhang, L., Liu, S., Zhang, C., Huang, X., Li, J., Zhao, N., & Wang, Z. (2009). PPARgamma transcriptionally regulates the expression of insulin‐degrading enzyme in primary neurons. Biochemical and Biophysical Research Communications, 383(4), 485‐ 490. 10.1016/j.bbrc.2009.04.047 19383491 · DOI
  8. Edbauer, D., Willem, M., Lammich, S., Steiner, H., & Haass, C. (2002). Insulin‐degrading enzyme rapidly removes the beta‐amyloid precursor protein intracellular domain (AICD). Journal of Biological Chemistry, 277(16), 13389‐ 13393. 10.1074/jbc.M111571200 11809755 · DOI
  9. Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., & Guenette, S. (2003). Insulin‐degrading enzyme regulates the levels of insulin, amyloid beta‐protein, and the beta‐amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences of the USA, 100(7), 4162‐ 4167. 10.1073/pnas.0230450100 12634421 PMC153065 · DOI
  10. Goodger, Z. V., Rajendran, L., Trutzel, A., Kohli, B. M., Nitsch, R. M., & Konietzko, U. (2009). Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. Journal of Cell Science, 122(Pt 20), 3703‐ 3714. 10.1242/jcs.048090 19773363 · DOI
  11. Grimm, M. O., Grimm, H. S., Patzold, A. J., Zinser, E. G., Halonen, R., Duering, M., Tschäpe, J. A., De Strooper, B., Müller, U., Shen, J., & Hartmann, T. (2005). Regulation of cholesterol and sphingomyelin metabolism by amyloid‐beta and presenilin. Nature Cell Biology, 7(11), 1118‐ 1123. 10.1038/ncb1313 16227967 · DOI
  12. Grimm, M. O., Mett, J., Stahlmann, C. P., Grosgen, S., Haupenthal, V. J., Blumel, T., Hundsdörfer, B., Zimmer, V. C., Mylonas, N. T., Tanila, H., Müller, U., Grimm, H. S., & Hartmann, T. (2015). APP intracellular domain derived from amyloidogenic beta‐ and gamma‐secretase cleavage regulates neprilysin expression. Frontiers in Aging Neuroscience, 7, 77 10.3389/fnagi.2015.00077 26074811 PMC4443740 · DOI
  13. Grimm, M. O., Mett, J., Stahlmann, C. P., Haupenthal, V. J., Blumel, T., Stotzel, H., Grimm, H. S., & Hartmann, T. (2016). Eicosapentaenoic acid and docosahexaenoic acid increase the degradation of amyloid‐beta by affecting insulin‐degrading enzyme. Biochemistry and Cell Biology, 94(6), 534‐ 542. 10.1139/bcb-2015-0149 27813426 · DOI
  14. Grimm, M. O., Mett, J., Stahlmann, C. P., Haupenthal, V. J., Zimmer, V. C., & Hartmann, T. (2013). Neprilysin and Abeta Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease. Frontiers in Aging Neuroscience, 5, 98 10.3389/fnagi.2013.00098 24391587 PMC3870290 · DOI
  15. Iwata, N., Tsubuki, S., Takaki, Y., Shirotani, K., Lu, B., Gerard, N. P., & Saido, T. C. (2001). Metabolic regulation of brain Abeta by neprilysin. Science, 292(5521), 1550‐ 1552. 10.1126/science.1059946 11375493 · DOI
  16. Kimberly, W. T., Zheng, J. B., Guenette, S. Y., & Selkoe, D. J. (2001). The intracellular domain of the beta‐amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch‐like manner. Journal of Biological Chemistry, 276(43), 40288‐ 40292. 10.1074/jbc.C100447200 11544248 · DOI
  17. Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., & Klein, W. L. (1998). Diffusible, nonfibrillar ligands derived from Abeta1‐42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences of the USA, 95(11), 6448‐ 6453. 10.1073/pnas.95.11.6448 9600986 PMC27787 · DOI · Paper page
  18. Leal, M. C., Magnani, N., Villordo, S., Buslje, C. M., Evelson, P., Castano, E. M., & Morelli, L. (2013). Transcriptional regulation of insulin‐degrading enzyme modulates mitochondrial amyloid beta (Abeta) peptide catabolism and functionality. Journal of Biological Chemistry, 288(18), 12920‐ 12931. 10.1074/jbc.M112.424820 23525105 PMC3642335 · DOI
  19. Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., & Selkoe, D. J. (2003). Enhanced proteolysis of beta‐amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron, 40(6), 1087‐ 1093. 10.1016/s0896-6273(03)00787-6 14687544 · DOI
  20. Li, H., Wu, J., Zhu, L., Sha, L., Yang, S., Wei, J., Ji, L., Tang, X., Mao, K., Cao, L., Wei, N., Xie, W., & Yang, Z. (2018). Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer's disease: possible mechanisms of IDE in T2D and AD. Bioscience Reports, 38(1), BSR20170862 10.1042/BSR20170862 29222348 PMC6435468 · DOI
  21. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real‐time quantitative PCR and the 2(‐Delta Delta C(T)) Method. Methods, 25(4), 402‐ 408. 10.1006/meth.2001.1262 11846609 · DOI · Paper page
  22. Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010). Decreased clearance of CNS beta‐amyloid in Alzheimer's disease. Science, 330(6012), 1774 10.1126/science.1197623 21148344 PMC3073454 · DOI · Paper page
  23. McLean, C. A., Cherny, R. A., Fraser, F. W., Fuller, S. J., Smith, M. J., Beyreuther, K., Bush, A. I., & Masters, C. L. (1999). Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Annals of Neurology, 46(6), 860‐ 866. 10.1002/1531-8249(199912)46:6<860:aid-ana8>3.0.co;2-m 10589538 · DOI
  24. Miller, B. C., Eckman, E. A., Sambamurti, K., Dobbs, N., Chow, K. M., Eckman, C. B., Hersh, L. B., & Thiele, D. L. (2003). Amyloid‐beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proceedings of the National Academy of Sciences of the USA, 100(10), 6221‐ 6226. 10.1073/pnas.1031520100 12732730 PMC156353 · DOI · Paper page
  25. Miners, J. S., Baig, S., Tayler, H., Kehoe, P. G., & Love, S. (2009). Neprilysin and insulin‐degrading enzyme levels are increased in Alzheimer disease in relation to disease severity. Journal of Neuropathology and Experimental Neurology, 68(8), 902‐ 914. 10.1097/NEN.0b013e3181afe475 19606063 · DOI
  26. Miners, J. S., Kehoe, P. G., & Love, S. (2008). Immunocapture‐based fluorometric assay for the measurement of insulin‐degrading enzyme activity in brain tissue homogenates. Journal of Neuroscience Methods, 169(1), 177‐ 181. 10.1016/j.jneumeth.2007.12.003 18221786 · DOI
  27. Miners, J. S., van Helmond, Z., Kehoe, P. G., & Love, S. (2010). Changes with age in the activities of beta‐secretase and the Abeta‐degrading enzymes neprilysin, insulin‐degrading enzyme and angiotensin‐converting enzyme. Brain Pathology, 20(4), 794‐ 802. 10.1111/j.1750-3639.2010.00375.x 20175776 PMC8094798 · DOI
  28. Morelli, L., Llovera, R. E., Mathov, I., Lue, L. F., Frangione, B., Ghiso, J., & Castano, E. M. (2004). Insulin‐degrading enzyme in brain microvessels: Proteolysis of amyloid beta vasculotropic variants and reduced activity in cerebral amyloid angiopathy. Journal of Biological Chemistry, 279(53), 56004‐ 56013. 10.1074/jbc.M407283200 15489232 · DOI
  29. Nalivaeva, N. N., Belyaev, N. D., & Turner, A. J. (2016). New insights into epigenetic and pharmacological regulation of amyloid‐degrading enzymes. Neurochemical Research, 41(3), 620‐ 630. 10.1007/s11064-015-1703-1 26376806 · DOI
  30. Nalivaeva, N. N., & Turner, A. J. (2019). Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy. British Journal of Pharmacology, 176(18), 3447‐ 3463. 10.1111/bph.14593 30710367 PMC6715594 · DOI
  31. Pardossi‐Piquard, R., Petit, A., Kawarai, T., Sunyach, C., Alves da Costa, C., Vincent, B., Ring, S., D'Adamio, L., Shen, J., Müller, U., St George Hyslop, P., & Checler, F. (2005). Presenilin‐dependent transcriptional control of the Abeta‐degrading enzyme neprilysin by intracellular domains of betaAPP and APLP. Neuron, 46(4), 541‐ 554. 10.1016/j.neuron.2005.04.008 15944124 · DOI
  32. Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013). Genome engineering using the CRISPR‐Cas9 system. Nature Protocols, 8(11), 2281‐ 2308. 10.1038/nprot.2013.143 24157548 PMC3969860 · DOI · Paper page
  33. Robinson, A., Grosgen, S., Mett, J., Zimmer, V. C., Haupenthal, V. J., Hundsdorfer, B., Stahlmann, C. P., Slobodskoy, Y., Müller, U. C., Hartmann, T., & Stein, R. & Grimm, M. O. (2014). Upregulation of PGC‐1alpha expression by Alzheimer's disease‐associated pathway: Presenilin 1/amyloid precursor protein (APP)/intracellular domain of APP. Aging Cell, 13(2), 263‐ 272. 10.1111/acel.12183 24304563 PMC4331788 · DOI
  34. Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J., & Klenk, D. C. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry, 150(1), 76‐ 85. 10.1016/0003-2697(85)90442-7 3843705 · DOI · Paper page
  35. Stargardt, A., Gillis, J., Kamphuis, W., Wiemhoefer, A., Kooijman, L., Raspe, M., Benckhuijsen, W., Drijfhout, J. W., Hol, E. M., & Reits, E. (2013). Reduced amyloid‐beta degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg‐AD mouse models. Aging Cell, 12(3), 499‐ 507. 10.1111/acel.12074 23534431 · DOI
  36. Tarasoff‐Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., Frangione, B., Blennow, K., Ménard, J., Zetterberg, H., Wisniewski, T., & de Leon, M. J. (2015). Clearance systems in the brain‐implications for Alzheimer disease. Nature Reviews. Neurology, 11(8), 457‐ 470. 10.1038/nrneurol.2015.119 26195256 PMC4694579 · DOI · Paper page
  37. Umeda, T., Tomiyama, T., Sakama, N., Tanaka, S., Lambert, M. P., Klein, W. L., & Mori, H. (2011). Intraneuronal amyloid beta oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. Journal of Neuroscience Research, 89(7), 1031‐ 1042. 10.1002/jnr.22640 21488093 · DOI
  38. von Rotz, R. C., Kohli, B. M., Bosset, J., Meier, M., Suzuki, T., Nitsch, R. M., & Konietzko, U. (2004). The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. Journal of Cell Science, 117(Pt 19), 4435‐ 4448. 10.1242/jcs.01323 15331662 · DOI
  39. Wang, S., Wang, R., Chen, L., Bennett, D. A., Dickson, D. W., & Wang, D. S. (2010). Expression and functional profiling of neprilysin, insulin‐degrading enzyme, and endothelin‐converting enzyme in prospectively studied elderly and Alzheimer's brain. Journal of Neurochemistry, 115(1), 47‐ 57. 10.1111/j.1471-4159.2010.06899.x 20663017 PMC2939954 · DOI
  40. Wolfe, M. S. (2020). Substrate recognition and processing by gamma‐secretase. Biochim Biophys Acta Biomembr, 1862(1), 183016 10.1016/j.bbamem.2019.07.004 31295475 PMC6899174 · DOI
  41. Xu, X., Zhou, H., & Boyer, T. G. (2011). Mediator is a transducer of amyloid‐precursor‐protein‐dependent nuclear signalling. EMBO Reports, 12(3), 216‐ 222. 10.1038/embor.2010.210 21293490 PMC3059912 · DOI
  42. Zhao, Z., Xiang, Z., Haroutunian, V., Buxbaum, J. D., Stetka, B., & Pasinetti, G. M. (2007). Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiology of Aging, 28(6), 824‐ 830. 10.1016/j.neurobiolaging.2006.05.001 16769157 · DOI

Cited by

Sorted by citations

Authors
Lauer, A. A., Mett, J., Janitschke, D., Thiel, A., Stahlmann, C. P., Bachmann, C. M., Ritzmann, F., Schrul, B., Müller, U. C., Stein, R., Riemenschneider, M., Grimm, H. S., Hartmann, T., & Grimm, M. O. W.
Affiliations
  • Saarland University (DE)
  • Universitätsklinikum des Saarlandes (DE)
  • Heidelberg University (DE)
  • Tel Aviv University (IL)
  • Department of Psychiatry and Psychotherapy Saarland University Hospital Homburg/Saar Germany
Corresponding author
Grimm, Marcus O. W.
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2020-10-31
Volume
19
Issue
11
Pages
e13264-e13264
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13264
PMC
PMC7681056
OpenAlex
W3097457964
Cited by
15
References
2
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 2
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Publications of the UdS (Saarland University) (cc-by)
Funders
  • EU Joint Programme – Neurodegenerative Disease Research
  • European Commission (211696)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
insulin-degrading enzyme, Alzheimer's disease, amyloid beta degradation, amyloid-beta production, APP processing, presenilin, gamma-secretase inhibition, amyloid-beta deposition, amyloid plaques
MeSH terms
Alzheimer Disease, Humans, Insulysin, Signal Transduction, Amyloid beta-Protein Precursor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review