Please use this identifier to cite or link to this item: doi:10.22028/D291-33603
Title: Regulatory feedback cycle of the insulin-degrading enzyme and the amyloid precursor protein intracellular domain: Implications for Alzheimer's disease
Author(s): Lauer, Anna A.
Mett, Janine
Janitschke, Daniel
Thiel, Andrea
Stahlmann, Christoph P.
Bachmann, Cornel M.
Ritzmann, Felix
Schrul, Bianca
Müller, Ulrike C.
Stein, Reuven
Riemenschneider, Matthias
Grimm, Heike S.
Hartmann, Tobias
Grimm, Marcus O. W.
Language: English
Title: Aging Cell
Volume: 19
Issue: 11
Publisher/Platform: Wiley
Year of Publication: 2020
Free key words: Alzheimer's disease
APP intracellular domain
Aβ homeostasis
insulin‐degrading enzyme
DDC notations: 500 Science
610 Medicine and health
Publikation type: Journal Article
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.
DOI of the first publication: 10.1111/acel.13264
Link to this record: urn:nbn:de:bsz:291--ds-336035
ISSN: 1474-9726
Date of registration: 22-Mar-2021
Description of the related object: Supporting Information
Related object:
Faculty: M - Medizinische Fakultät
NT - Naturwissenschaftlich- Technische Fakultät
Department: M - Medizinische Biochemie und Molekularbiologie
M - Neurologie und Psychiatrie
NT - Biowissenschaften
Professorship: M - Prof. Dr. Tobias Hartmann
M - Prof. Dr. Matthias Riemenschneider
M - Jun.-Prof. Dr. Bianca Schrul
NT - Keiner Professur zugeordnet
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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