Kinoshita A, Whelan CM, Berezovska O, Hyman BT.
The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells.
J Biol Chem. 2002 Aug 9;277(32):28530-6.
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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.
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.
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