Caspase-Independent Pathway of Amyloid-Beta Cytotoxicity

Neuronal loss induced by oligomerized amyloid beta (Aß) peptide is an important feature of Alzheimer’s disease. It has been proposed that apoptotic cell death, the body’s own suicide program to ensure the elimination of dangerous cells, may contribute to the neuronal loss in AD. However, the inhibition of caspases, a family of proteases that execute apoptosis, only partially relieves the cytotoxicity induced by AD, which suggests that other, caspase-independent cell death pathways must exist. In previous work, Dr. Degterev defined a novel caspase-independent cell death pathway named “aponecrosis.” He identified two inhibitors (ANI1 and ANI2) that specifically inhibit aponecrosis in a number of cell types. The major goal of this study is to identify the molecular mechanism of the aponecrotic pathway induced by Aß in vitro and to define its role in animal models of AD. Ultimately, this work could lead to the identification of novel molecular targets for drug interventions in AD, and ANIs may serve as potential prototypes and/or target compounds in the development of new AD treatments.