Identification of novel roles of the amyloid precursor protein in signal transduction
By: by Matthew Robert Hass
Published: 2007
Language: eng
Number of pages: 209
Description: The focus of this dissertation was to investigate the physiological function of the amyloid precursor protein (APP), with the thought that a more thorough understanding of its normal function could provide insights into the pathological process underlying Alzheimer's disease. APP has been shown to be cleaved by the presenilins to release the Aβ peptide that is thought to be a causative factor in Alzheimer's disease. It had been suggested that APP signals to the nucleus through complex formation with the adaptor protein Fe65 and the histone acetyltransferase Tip60. Here we show that cleavage of APP by the presenilins is not required for APP to be able to activate transcription through Tip60, in contrast to the absolute requirement of the gamma-secretase cleavage for Notch signaling. This signaling pathway requires APP recruitment of Tip60 to the membrane and CDK phosphorylation and stabilization of Tip60. Similarly, we have found that APP stabilizes the adaptor protein Fe65 through membrane recruitment and phosphorylation of Fe65 at a conserved Akt consensus site. Additionally, we provide evidence for phosphorylation of Fe65 by the DNA damage responsive kinase ATM and show that Fe65 wild-type but not the Akt site mutant protects against DNA damage induced cell death. Furthermore, we show that APP regulates the activity and levels of the tumor suppressor protein p53. APP recruits p53 to the membrane through binding of Fe65 to p53, which leads to the destabilization of p53. This function of APP may be linked to its proteolysis because preventing cleavage with gamma-secretase inhibitors potentiates the p53 suppression by APP. Additionally, Alzheimer's disease causing mutations in APP that enhance amyloid production exhibit decreased ability to inhibit p53.

This suppression of p53 by APP leads to decreased DNA damage induced cell death. We confirm that this regulation may occur in vivo in the brain as presenilin conditional knockout mice brain that have elevated APP C-terminal fragments and Fe65 levels exhibit decreased levels of the p53 family member p73. Lastly, we show that the cytoplasmic E3 ligase parkin is a component of the APP, Fe65, and p53 complex and is required for efficient p53 turnover.
Notes: Thesis (Ph.D., Division of Medical Sciences (Neurobiology))--Harvard University, 2007.

Includes bibliographical references.