The Alzheimer's plaques, tangles and memory deficits may have a common origin. Part IV: can calpain act as alpha-secretase?

Abnormality of protease activities and imbalance of intracellular calcium are two most salient aberrant events in Alzheimer's disease (AD). As such, calcium-dependent proteases such as calpain, as a critical link between these two events, must play a key role in the pathogenesis of AD, particularly in the abnormal processing of beta-amyloid precursor protein. Because alpha-secretase in this process appears to be a calcium-dependent protease and its enzymatic characteristics are impressively similar to those of calpain, a challenging possibility arises: Calpain might act as alpha-secretase in vivo. However, as the experimental evidence both for and against this possibility is compelling, the issue currently remains as a theoretical dilemma in which a central question is whether calpain, a cytosolic enzyme, can somehow reach the cell surface. This difficult issue needs to be addressed now. As a first attempt to explore the issue, we propose a working model for the membrane orientation of calpain and suggest several experiments that will critically test this model. The quest to this dilemma will not only impact our understanding of AD, but may also expand the current knowledge about Ca2+ signal transduction pathway. Finally, we discuss several competing models and the potential role of presenilins as "regulators" of alpha-secretase. It is of interest to note that some of our previous theoretical predictions have been experimentally observed.