Amyloid Precursor Protein Processing Through a Novel Pathway in Alzheimer's Disease

We aim to study the metabolism of APP fragments generated by the novel eta-secretase pathway to determine if there are changes in AD and to help us form a comprehensive model of APP processing.

Although APP, the parent protein of Abeta, was discovered 40 years ago, it wasn’t until recently that a new cleavage product of APP was detected in human biofluids. Eta-secretase was found to cut APP to generate AETA. AETA has been shown to be very important in processes that play a role in memory formation, and its levels change in mouse models when prospective AD therapies are administered. Not much is known about AETA in humans, and thus, we want to develop a method to measure how quickly AETA is produced and cleared in a healthy older human and then compare this to AETA metabolism in AD.

The eta-secretase pathway of APP was discovered only 10y ago. Recent reports indicate that a resulting cleavage product, AETA, has an important biological function. There are only a handful of studies reporting the existence of eta-secretase-APP cleavage products in human biofluids, and that AETA levels change in AD in tests of a handful of subjects. In our study, we will not only study whether there are changes in AETA in AD in a larger cohort of 50 subjects, but we will also measure the production and clearance of AETA, thus providing us with more information on the dynamic processing of APP.

AETA has been found to be higher during BACE inhibitor treatment. BACE inhibitor clinical trials failed due to cognitive worsening, but attempts to revitalize these drugs in low-dose forms as a preventative strategy for AD are ongoing. Given the potential that AETA might contribute to BACE inhibitor-related adverse effects, it is extremely important to study normal and AD-related AETA metabolism in humans, which, until now, no one has done. Our results could be informative for future low-dose BACE inhibitor trial programs and give us a better understanding of the complex processing of APP.