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Inhibition of protein degradation induces accumulation of novel fragments of amyloid precursor protein (APP)
Dissertation   Open access

Inhibition of protein degradation induces accumulation of novel fragments of amyloid precursor protein (APP)

Haizhi Wang
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2016
DOI:
https://doi.org/10.17918/00010103
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Abstract

Neurosciences Neurobiology
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.

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