Clustering hinders APP α-secretase processing in the plasma membrane

Authors:

Kerstin Pinkwart, Thorsten Lang

Keywords:

Alzheimer’s disease; Aβ-peptide; amyloid precursor protein; α-secretase cleavage; amyloidogenic pathway

Abstract:

Alzheimer’s disease (AD) is associated with the extracellular accumulation of neurotoxic Aβ-peptides in the brain. Aβ-peptides are produced via an amyloid precursor protein (APP) cleavage pathway that is initiated by the β-secretase. The majority of APP circumvents the amyloidogenic pathway due to α-secretase cleavage at the plasma membrane.

In this study, we set out to identify potential mechanisms limiting α-cleavage. We employed isolated cell membranes to study α-secretase cleavage in the absence of APP delivery to the plasma membrane and internalization. We distinguish a readily cleavable and a cleavage-resistant APP pool. The cleavage-resistant and most likely immobile APP pool is organized in clusters and by this could escape the amyloidogenic pathway.

In sum, our results identify that α-secretase cleavage at the plasma membrane occurs rapidly though in an incomplete manner due to the presence of cleavage-resistant APP clusters.

< Back to publications

Full article >