Caspase Activation in Alzheimer's Disease: Early to Rise and Late to Bed

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It has been almost 15 years since the first report of apoptosis as a major mechanism of cell death associated with Alzheimer’s disease (AD). Presently, whether neurons die through apoptosis or some other pathway is still a hotly debated issue. However, mounting evidence suggests a role for the activation of caspases and cleavage of critical cellular proteins during the progression of AD. The activation of apoptotic pathways may represent s protracted battle due to the presence of various anti-apoptotic molecules such as Bcl 2 whereby neurons do not immediately execute the apoptotic program but caspase activation occurs discretely at some low level. During this time, caspase cleavage of the amyloid-precursor protein (APP), the adaptor protein GGA3 involved with beta-amyloid production, and tau may promote the formation of beta-amyloid (Aβ) and neurofibrillary tangles (NFTs). Thus, not only may activation of caspases represent a terminal event associated with AD (i.e. cell death), but also a proximal event that promotes the pathology underlying this disease. Therefore, therapeutics aimed at preventing the activation and execution of apoptosis may provide an effective means of treating AD.