It is known that elevated cholesterol promotes amyloidogenesis, but the mechanism has not previously been clear. In this study the structure of the transmembrane C-terminal domain of the amyloid precursor protein (C99) was determined using NMR spectroscopy and found to have several surprising features to provide insight into how this protein is proteolytically processed in the pathway to formation of amyloid-beta, which is closely associated with the etiology of Alzheimer’s disease.  While C99 does form dimers, it does so with low and possibly non-physiological affinity.  It was also discovered that C99 is a cholesterol binding protein, with a Kd well within the physiological range of membrane cholesterol concentrations.  Based on this and additional data, we propose a unifying model for how cholesterol promotes the amyloidogenic pathway. We have also tested the hypothesis that C99 has an intrinsic affinity for raft-like liquid ordered (Lo) domains and that its domain preference is regulated by cholesterol binding. This work represents a collaboration with the lab of Anne Kenworthy (also at Vanderilt) and was supported by NIGMS and the Alzheimer's Association.

Structure, dimerization, and cholesterol binding of the amyloid precursor protein transmembrane C99 domain and amyloidogenesis

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.