Investigators such as Luciano D'Adamio and Rachel Neve have both argued for several years that the C-terminus of APP is toxic, and plays an important role the pathophysiology of Alzheimer's disease. The discovery by Sudhoff's group that APP promotes transcription via Fe65 provided a clear functional role for the C-terminus of APP. The current paper connects APP mediated transcription with APP mediated apoptosis, by showing that the transcription factor Tip60 is required for apoptosis mediated by the C-terminus of APP. Whether or not this is important to the pathophysiology of AD remains unclear. However, understanding the function of the C-terminus of APP is clearly going to be important because gamma-secretase inhibitors are a putative treatment for Alzheimer patients. These agents increase the amount of C-terminal APP fragments, which could have deleterious effects if the C-terminal fragments are toxic.

View all comments by Benjamin Wolozin

This nice paper evokes another question and mechanism on Abeta and APP-CT whether toxic Aβ affects APP to enhance the production of APP-C58 as a downstream effector.

View all comments by Hiroshi Mori