Biology subjects

Sergeant, N.

Publications and source records attributed to Sergeant, N..

3 recordsLinked to original sources

bioRxiv2026

APP metabolism is regulated by p97/VCP through an autophagy and endolysosome-dependent mechanism

Deregulation of amyloid precursor protein (APP) metabolism leads to the production of pathological proteoforms of A{beta} peptides, which ultimately form amyloid deposits, a primary pathological feature of Alzheimers disease (AD). The accumulation of misfolded proteins and alterations in protein degradation systems, such as the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and autophagy-lysosomal pathways, also contribute to AD development. The Valosin-Containing Protein AAA-ATPase (p97/VCP) is a crucial regulator of proteostasis, facilitating the clearance of misfolded proteins by the proteasome and other protein degradation systems. Here, we investigated whether VCP influences APP processing. Reducing VCP expression or inhibiting its ATPase activity led to the accumulation of mature, full-length APP in cells, thereby decreasing APP trafficking to the cell surface. Downstream of APP-CTFs secretase processing, p97/VCP modulates APP-CTFs cleavage and degradation via autophagy and endolysosomal-dependent mechanisms. Our findings demonstrate that VCP is involved in APP metabolism at two levels: controlling APP trafficking within the cell secretory pathway and regulating autophagy-dependent degradation of APP-CTFs, suggesting a potential role for VCP in the APP deregulation observed in AD.

cell biology↗

bioRxiv2021

A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration

A structure-activity relationship has enabled us to identify two molecules, MAGS02-14 and PEL24-199, sharing a {beta}-secretase modulatory effect but having or not a lysosomotropic activity, respectively. More importantly, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. However, which of the lysosomotropic and/or {beta}-secretase modulating activities is necessary for the pharmacological effect in vivo remains ill-defined. To address this question, the THY-Tau22 transgenic model of NFD was treated for 6 weeks in a curative paradigm and short-term memory, Tau burden, and inflammatory processes were studied. PEL24-199, possessing only the {beta}-secretase modulatory activity, was shown to restore the short-term memory and to reduce NFD. This effect was associated with reduced phosphorylation of Tau, increased phosphatase expression, and a decrease of astrogliosis. Our results therefore suggest that the lysosomotropic activity may be dispensable for the effect on both A{beta} and Tau pathologies.

pharmacology and toxicology↗

bioRxiv2018

Contribution of the endosomal-lysosomal and proteasomal systems in Amyloid-β Precursor Protein derived fragments processing

A{beta} peptides, the major components of amyloid deposits of Alzheimers disease, are released following sequential cleavages by secretases of its precursor named the amyloid precursor protein (APP). In addition to secretases, degradation pathways, in particular the endosomal/lysosomal and proteasomal systems have also been reported to contribute to APP processing. However, the respective role of each of these pathways towards APP metabolism remains to be established. To address this, we used HEK 293 cells and primary neurons expressing full-length APPWT or the {beta}-secretase-derived C99 fragments ({beta}-CTFs) in which degradation pathways were selectively blocked using pharmacological drugs. APP metabolites, including carboxy-terminal fragments (CTFs), soluble APP (sAPP) and A{beta} peptides were studied. In this report, we show that APP-CTFs produced from endogenous or overexpressed full-length APP are mainly processed by {gamma}-secretase and the endosomal/lysosomal pathway, while in sharp contrast, overexpressed C99 alone is mainly degraded by the proteasome and to a lesser extent by {gamma}-secretase.

neuroscience↗