Alpha- and beta-secretase
This group is part of the Alzheimer`s disease research program. The Willem / Lammich group is focusing on the Alzheimer`s disease associated beta-secretase (BACE1) and alpha-secretase (ADAM10). The generation of amyloid peptides (Abeta) from the amyloid precursor protein (APP) is initiated by BACE1, whereas subsequent gamma-secretase cleavage mediated by presenilin-1 produces Abeta peptides mainly of 40 or 42 amino acids long.
In addition, alternative beta'-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Abeta (11-40/42) peptides, but the functional significance or pathological impact is unknown. ADAM10 and BACE2 cleave APP with an antiamyloidogenic activity (Figure 1).
We focus on the identification of cellular mechanisms involved in the physiological and pathophysiological regulation of BACE1. Therefore we analyse the function of BACE in the context of animal models (mouse and zebrafish) and in AD as well as in Down syndrome, which both show plaque pathology. Furthermore we are interested in the translational regulation mechanisms which control the expression of AD secretases.
Alzheimer's disease (AD) is the most common cause of progressive cognitive decline in the aged population. Pathologically AD is characterized by the accumulation of senile plaques, which are predominantly composed of the amyloid β-peptide (Aβ). Aβ is derived from the membrane bound beta-amyloid precursor protein (βAPP) by sequential proteolytic cleavage. β-secretase (BACE) and γ-secretase generate Aβ, whereas processing of βAPP by α-secretase prevents Aβ formation. Therefore proteolytic processing of βAPP through α-, β- and γ-secretase determines the generation of Aβ. Our research focus: We analyze the subcellular localization of βAPP and its processing secretases. Further we study the influence of trafficking and sorting of BACE, α-, β- and γ-secretase on enzyme activity and Aβ generation.