Cathepsin D: Analysis of its potential role as an amyloid beta degrading protease

Lisa Gallwitz, Lina Schmidt, André R.A. Marques, Andreas Tholey, Liam Cassidy, Irem Ulku, Gerhard Multhaup, Alessandro Di Spiezio, Paul Saftig

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Abstract

Proteolysis catalyzed by the major lysosomal aspartyl protease cathepsin-D (CTSD) appears to be of pivotal importance for proteostasis within the central nervous system and in neurodegeneration. Neuronal Ceroid Lipofuscinosis (NCL) type 10 is caused by a lack of CTSD leading to a defective autophagic flow and pathological accumulation of proteins. We previously demonstrated a therapeutic-relevant clearance of protein aggregates after dosing a NCL10 mouse model with recombinant human pro-cathepsin-D (proCTSD). Similar results could be achieved in cells and mice accumulating α-synuclein. Prompted by these positive effects and our in vitro findings showing that cathepsin-D can cleave the Alzheimer's Disease (AD)-causing amyloid beta peptides (Aβ), we envisaged that such a treatment with proCTSD could similarly be effective in clearance of potentially toxic Aβ species. We demonstrated that CTSD is able to cleave human Aβ1–42 by using liquid chromatography-mass spectrometry. Intracerebral dosing of proCTSD in a NCL10 (CTSD knockout) mouse model revealed uptake and processing of CTSD to its mature and active form. However, the re-addition of CTSD did not obviously affect intracellular APP processing or the generation of soluble APP and Aβ-species. ProCTSD treated HEK cells in comparison with untreated cells were found to contain comparable levels of soluble and membrane bound APP and Aβ-species. Also, the early intracranial application (P1 and P20) of proCTSD in the 5xFAD mouse model did not change Aβ pathology, plaque number and plaque composition and neuroinflammation, however we observed an increased level of Aβ1–42 in the CSF. Our data confirm proteolytic cleavage of human Aβ1–42 by CTSD but exclude a prominent role of CTSD in APP processing and Aβ degradation in our in vitro and in vivo models.

Original languageEnglish
Article number105919
JournalNeurobiology of Disease
Volume175
DOIs
Publication statusPublished - Dec 2022

Keywords

  • Alzheimer's disease
  • Amyloid beta
  • Amyloid precursor protein
  • Cathepsin-D
  • Lysosome
  • Neuronal ceroid lipofuscinosis 10
  • Proteolysis

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