ABSTRACT
This chapter focuses on the interaction of presenilins with apoptototic processes. It begins with an overview of the field of apoptosis, covering methods and terminology. We discuss how studies of apoptosis can help us understand the pathophysiology of neurodegenerative diseases and how apoptotic process may actually impact on neurolodegenerative illnesses. We will then review research performed implicating presenilins with apoptosis. Wildtype presenilin 2 (PS2) participates enhances apoptosis induced by trophic withdrawal, and mutations in both presenilins sensitize cells to cell death induced by a wide range of factors, including Aβ, trophic withdrawal, tumor necrosis factor and ceramide. The explanation for this profile of biochemical sensitivity is becoming clearer through analysis of the signal transduction pathways regulated by presenilins. Biochemical studies show that presenilins acts as an endogenous inhibitors of apoptotic cascade. PS2 strongly inhibits both Jun Kinase and NFκB activity. Loss or gain of activity is problematic for the cells. Overexpression of wildtype PS2 greatly reduces NFκB activity which removes an important neuroprotective factor from the cell and renders the cell vulnerable to cell death. Mutant forms of PS2 are inactive. This removes an endogenous ‘shock absorber’ from the cells and increases the cells response to agents that activate the Jun Kinase/NFκB cascade. This hyper-responsiveness renders the cells vulnerable to stress. Finally, we will relate this work to the larger field of Alzheimer’s research and show how the work connecting presenilins with apoptosis may integrate into a broader conceptual model for the pathophysiology of Alzheimer’s disease.
