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

David Hicks, Alys Jones, Stuart Pickering-Brown, Nigel Hooper

Research output: Contribution to journalArticlepeer-review


Alzheimer’s disease (AD) is a neurodegenerative condition, of which one of the cardinal pathological hallmarks is the extracellular accumulation of amyloid beta (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 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 extra-nuclear APP holoprotein and its nuclear Cterminal
fragment. The latter (amyloid precursor protein intracellular domain) was shown to predominantly localise to nucleoli, from which TDP-43 was excluded. Furthermore, neither over-expression of each of the APP isoforms nor siRNA-mediated knockdown of APP had any effect on TDP-43 expression. Doxycycline-stimulated over-expression of TDP-43 was explored in an inducible cell line. Over-expression 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.
Original languageEnglish
JournalBioscience reports
Publication statusAccepted/In press - 6 Apr 2020


Dive into the research topics of 'The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43'. Together they form a unique fingerprint.

Cite this