Inhibition of protein degradation induces accumulation of novel fragments of amyloid precursor protein (APP)
Year: 2016
Type: dissertation
Abstract: Alzheimer's disease is a progressive neurodegenerative disease and the most common type of dementia. One of AD hallmarks is the deposition of amyloid [beta] (A-[beta]), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via [alpha]-/ [beta]- and [gamma]-secretases. APP is also actively degraded by protein degradation systems. By pharmacologically inhibiting protein degradation with ALLN, we observed an accumulation of heretofore undocumented APP fragments (CTFs). The two major novel CTFs migrated around 15 and 25 kD. The process was independent of cytotoxicity or protein synthesis. The build-up of the novel CTFs are not mediated by proteasome or calpain inhibition, but by cathepsin inhibition. Moreover, these novel CTFs are not generated by increased amount of BACE. Here, we name the CTF of 25 kD as [eta]-CTF. Our data suggests that under physiological conditions, a subset of APP undergoes alternative processing and the intermediate products, the 15 kD- and the 25 kD-CTFs ([eta]-CTF) get rapidly degraded/ processed via the protein degradation machinery, specifically, cathepsin.
DOI: 10.17918/00010103
Authors: Haizhi Wang, Aleister Saunders
Institution: Drexel University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4400180075