University of Sherbrooke, Canada
Title: The role of apoptotic mechanisms in the pathophysiology of Alzheimer’s Disease
Rona Graham completed her Ph.D in 2006 and did her postdoctoral studies at the University of BC. She is now an assistant professor at the University of Sherbrooke and holds the canada research chair in neurodegenerative disease. Currently she has more than 45 publications, many in high impact journals, is editorial review board member for frontiers in genetics disorders and is involved in numerous outreach activities in the community.
Activation of caspases and proteolytic cleavage of caspase substrates is an early, critical cellular event in several neurodegenerative diseases. Caspase-6 (casp6) in particular has emerged as an important player. Casp6 has been shown to function as an initiator caspase through its ability to cleave and activate other caspases and activation of casp6 is observed prior to the clinical and pathological diagnosis of both Alzheimer disease (AD) and Huntington disease. In support of this, recent studies suggest caspase activation precedes and leads to tangle formation in AD. This includes an important role for casp6 in axonal degeneration and memory impairment, further underscoring the importance of this protease in neurodegenerative pathways. Despite the wealth of data regarding casp6 in human AD brain, only limited details are available in mouse models which enable a detailed assessment of all aspects of neurodegeneration including delineation of important early primary events. Similar to human AD brain, we detect early activation of casp6 in a pre-symptomatic mouse model of AD, prior to obvious degeneration and activation of other caspases. Furthermore, through yeast-2-hybrid studies, we have identified, and validated, novel casp6 interactors STK3 and DAXX. Assessment of AD murine tissues reveals increases in DAXX and STK3 are detected early and alterations in post translational modifications observed. Casp6 now links STK3 and DAXX with AKT, JNK and histones in the pathogenesis of AD and highlights an early role for these substrates in neurodegenerative pathways. These data provide strong support for casp6 as a potential target for therapeutic intervention in AD.