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Article type: Research Article
Authors: Buoso, Ericaa | Biundo, Fabrizioa | Lanni, Cristinaa | Schettini, Gennarob | Govoni, Stefanoa | Racchi, Marcoa; *
Affiliations: [a] Department of Drug Sciences, Pharmacology Unit, Center of Excellence in Applied Biology, University of Pavia, Pavia, Italy | [b] Department of Oncology, Biology and Genetics, University of Genova, Genova, Italy
Correspondence: [*] Correspondence to: Marco Racchi, PhD, Department of Drug Sciences, Pharmacology Unit, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy. Tel.: +39 0382 987738; Fax: +39 0382 987405; E-mail: [email protected].
Abstract: The amyloid-β protein precursor (AβPP) can be processed by either the amyloidogenic or the non-amyloidogenic pathway; both pathways lead to release of the AβPP intracellular C-terminal domain (AICD). AICD involvement in signal transduction within Fe65/Tip60 complex is one of the most discussed mechanisms, and different models have been hypothesized to explain the role of AICD within this complex. The analysis of these models in relation to the degradation processes highlights the discrepancy among AICD localization, function, and degradation, leading to the hypothesis that a signaling mechanism may exist which allows AβPP proteolysis to generate either a transcriptionally active fragment or an inactive one with different involvement of proteasome and IDE (insulin-degrading enzyme). Our work aimed to analyze the functional role of AICD within the Fe65/Tip60 complex considering the AICD degradation processes. Our data suggest a correlation between the role of AICD in gene regulation and its removal operated by proteasome activity. Moreover, treatments with IDE inhibitor underlined the presence of an alternative mechanism involved in AICD removal when the latter is not exerting nuclear activity, thus providing clearer support for the existence of at least two mechanisms as previously suggested.
Keywords: AβPP, AICD, Fe65, IDE, proteasome, Tip60
DOI: 10.3233/JAD-2012-111961
Journal: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 393-405, 2012
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