Details

Autor(en) / Beteiligte

• Beher, Dirk
• Wrigley, Jonathan D. J.
• Owens, Andrew P.
• Shearman, Mark S.

Titel

Generation of C‐terminally truncated amyloid‐β peptides is dependent on γ‐secretase activity

Ist Teil von

• Journal of neurochemistry, 2002-08, Vol.82 (3), p.563-575

Ort / Verlag

Oxford, UK: Blackwell Science Ltd

Erscheinungsjahr

2002

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Aberrant production of amyloid‐β peptides by processing of the β‐amyloid precursor protein leads to the formation of characteristic extracellular protein deposits which are thought to be the cause of Alzheimer's disease. Therefore, inhibiting the key enzymes responsible for amyloid‐β peptide generation, β‐ and γ‐secretase may offer an opportunity to intervene with the progression of the disease. In human brain and cell culture systems a heterogeneous population of amyloid‐β peptides with various truncations is detected and at present, it is unclear how they are produced. We have used a combination of surface enhanced laser desorption/ionization time‐of‐flight mass spectrometry (SELDI‐TOF MS) and a specific inhibitor of γ‐secretase to investigate whether the production of all amyloid‐β peptide species requires the action of γ‐secretase. Using this approach, we demonstrate that the production of all truncated amyloid‐β peptides except those released by the action of the nonamyloidogenic α‐secretase enzyme or potentially beta‐site βAPP cleaving enzyme 2 depends on γ‐secretase activity. This indicates that none of these peptides are generated by a separate enzyme entity and a specific inhibitor of the γ‐secretase enzyme should havethe potential to block the generation of all amyloidogenicpeptides. Furthermore in the presence of γ‐secretase inhibitors, the observation of increased cleavage of the membrane‐bound βAPP C‐terminal fragment C99 by α‐secretase suggests that during its trafficking C99 encounters compartments in which α‐secretase activity resides.