Regulation of the non-amyloidogenic processing pathway of β-amyloid precursor protein (APP) in Alzheimer’s disease.
Prof. Dr. Christian Haass, Dr. Anja Capell
Sequential proteolytic processing of the β-amyloid precursor protein (βAPP) can occur in two distinct ways: (1) in the amyloidogenic pathway, the first cleavage is performed by β-secretase and results after processing by β,-secretase in Aβ (amyloid beta) peptide formation, leading to Alzheimer pathology, and (2) in the non-amyloidogenic pathway, in which βAPP is firstly cut by α-secretase within the Aβ sequence thereby preventing Aβ peptide formation. As α- and β-secretases compete for their substrate βAPP, an increased processing of βAPP by α-secretase can reduce Aβ generation.
Two important βAPP cleaving α-secretases are ADAM10 (a disintegrin and metalloprotease 10) and ADAM17. Both are expressed as inactive zymogens, which are processed into mature enzymes by proteolytic cleavage of their prodomains and complex glycosylations in the Golgi apparatus. Subsequently ADAM10/17 are transported to the plasma membrane to access their substrates. Not only the extent of maturation but also the cellular sorting of these two proteases decide about their accessibility towards their substrates and thus the extent of α-shedding of βAPP.
Aim of my work is to investigate potential regulatory mechanisms that affect transport and maturation of the α-secretases.
- This project is funded by the Helmholtz Association.