The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

• Published in: Bioscience reports Vol. 40; no. 4
• Main Authors: Hicks, David A, Jones, Alys C, Pickering-Brown, Stuart M, Hooper, Nigel M
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 30.04.2020
• Subjects: Alzheimer Disease - pathology; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - metabolism; Cell Line, Tumor; Cell Nucleus - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Knockdown Techniques; Humans; Molecular Bases of Health & Disease; Neurons - cytology; Neurons - metabolism; Neuroscience; Proteolysis; RNA, Small Interfering - metabolism; Signaling; BACE1; Alzheimers disease; Gene regulation; TDP-43; Amyloid precursor protein; proteolysis
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20200435

Alzheimer's disease (AD) is a neurodegenerative condition, of which one of the cardinal pathological hallmarks is the extracellular accumulation of amyloid β (Aβ) peptides. These peptides are generated via proteolysis of the amyloid precursor protein (APP), in a manner dependent on the β-secretase, BACE1 and the multicomponent γ-secretase complex. Recent data also suggest a contributory role in AD of transactive response DNA binding protein 43 (TDP-43). There is little insight into a possible mechanism linking TDP-43 and APP processing. To this end, we used cultured human neuronal cells to investigate the ability of TDP-43 to interact with APP and modulate its proteolytic processing. Immunocytochemistry showed TDP-43 to be spatially segregated from both the extranuclear APP holoprotein and its nuclear C-terminal fragment. The latter (APP intracellular domain) was shown to predominantly localise to nucleoli, from which TDP-43 was excluded. Furthermore, neither overexpression of each of the APP isoforms nor siRNA-mediated knockdown of APP had any effect on TDP-43 expression. Doxycycline-stimulated overexpression of TDP-43 was explored in an inducible cell line. Overexpression of TDP-43 had no effect on expression of the APP holoprotein, nor any of the key proteins involved in its proteolysis. Furthermore, increased TDP-43 expression had no effect on BACE1 enzymatic activity or immunoreactivity of Aβ1-40, Aβ1-42 or the Aβ1-40:Aβ1-42 ratio. Also, siRNA-mediated knockdown of TDP-43 had no effect on BACE1 immunoreactivity. Taken together, these data indicate that TDP-43 function and/or dysfunction in AD is likely independent from dysregulation of APP expression and proteolytic processing and Aβ generation.