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Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments

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Department of Biology, College of Art and Sciences, Drexel University, Philadelphia, Pennsylvania 19104, United States
Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, Pennsylvania 19104, United States
§ Harvard University and Massachusetts General Hospital, Boston, Massachusetts 02114, United States
Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, Pennsylvania 19104, United States
*Address: 424 PISB 3245 Chestnut St., Philadelphia, PA 19104. E-mail: [email protected]. Telephone: (215) 895-6772.
Cite this: Biochemistry 2015, 54, 18, 2806–2816
Publication Date (Web):April 24, 2015
Copyright © 2015 American Chemical Society

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    Abstract Image

    Alzheimer’s disease (AD) is characterized by the deposition of amyloid β (Aβ), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via α-, β-, and γ-secretases. APP is also actively degraded by protein degradation systems. By pharmacologically inhibiting protein degradation with ALLN, we observed an accumulation of several novel APP C-terminal fragments (CTFs). The two major novel CTFs migrated around 15 and 25 kDa and can be observed across multiple cell types. The process was independent of cytotoxicity or protein synthesis. We further determine that the accumulation of the novel CTFs is not mediated by proteasome or calpain inhibition, but by cathepsin L inhibition. Moreover, these novel CTFs are not generated by an increased amount of BACE. Here, we name the CTF of 25 kDa as η-CTF (eta-CTF). Our data suggest that under physiological conditions, a subset of APP undergoes alternative processing and the intermediate products, the 15 kDa CTFs, and the η-CTFs aret rapidly degraded and/or processed via the protein degradation machinery, specifically, cathepsin L.

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