A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Robert J. Andrew; Katherine A. B. Kellett; Gopal Thinakaran; Nigel M. Hooper

doi:10.1074/jbc.R116.746032

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis *

From the ^‡Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, Illinois 60637 and
the ^§Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom

↵1 To whom correspondence may be addressed. Tel.: 773-834-3771; E-mail: rjandrew{at}uchicago.edu.
↵2 To whom correspondence may be addressed. Tel.: 44-161-306-5765; E-mail: nigel.hooper{at}manchester.ac.uk.

Abstract

Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-β. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical α-, β-, and γ-secretases is simplistic, with the discovery of a number of novel APP secretases (including δ- and η-secretases, alternative β-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.

Footnotes

↵* This work was supported by Alzheimer's Research UK (PhD2012-5), the Dr Donald Dean Fund in Dementia Research, and the University of Manchester (to N. M. H.). This work was also supported by National Institutes of Health Grants AG019070 and AG051230 (to G. T.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.