The History of APP Cleavage

The amyloid b-peptide (Ab) is one of the hallmarks of AD. Ab derives from a transmembrane protein, the amyloid precursor protein (APP) [85], through two sequential cleavages. APP is first cleaved by b-secretase BACE 1 (the b-site APP cleavage enzyme), in its luminal domain to generate a secreted ectodomain (sAPPb) and a membrane-bound APP carboxyl terminal fragment (CTFb). This 10-kDa C-terminal stub of APP is subsequently the substrate for b-secretase or presenilin 1 [86], which cleaves the transmembrane domain of APP to release two Ab peptides of 40 and 42 amino acids [85].

In an alternative non pathogenic pathway, APP is cleaved within the Ab sequence by a-secretase (belonging to the ADAM family of metalloproteases), which generates other secreted derivates known as sAPPa and APP CTFa. Like CTFb, CTFa can be cleaved by g-secretase yielding CTFg and a fragment designated p3 [87]. Since a-cleavage cuts APP within the Ab region it prevents Ab formation and, as a-and b-cleavage compete for their substrate APP, it is crucial to understand the mechanism which regulates and controls the access of these enzymes to APP.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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