THE ALZHEIMER'S PLAQUES, TANGLES AND MEMORY DEFICITS MAY HAVE A COMMON ORIGIN - PART IV: CAN CALPAIN ACT AS a-SECRETASE?

Ming Chen¹ and Hugo L. Fernandez²

^1,2 Neuroscience Research Laboratory, Medical Research Service (151), Bay Pines VA Medical Center, Bay Pines, Florida 33744, USA. ² Department of Pharmacology and Therapeutics; Department of Neurology and bDepartment of Physiology and Biophysics, University of South Florida College of Medicine, Tampa, Florida, 33612, USA

Received 11/25/98 Accepted 12/4/98

4. CONCLUSIONS

The identity of a-secretase remains to be unambiguously defined but its regulated nature points to a narrow area of search, and the largely homogeneous C-terminus of APPs suggests a single protease being responsible for APP a-processing. This would justify the identification of a-secreatse as a feasible project. Our theoretical analysis indicates that it is the state of a-secretase, or more precisely, it is the state of the regulatory factor behind this protease, Ca2+, that governs the outcomes of APP processing in vivo. The enzymatic characteristics of a-secretase are significantly similar to those of calpain, and calpain is known to be critically implicated in memory process and in tau degradation. It is therefore reasonable to conclude that the roles played by calpain (and Ca2+) are of paramount importance for unraveling the AD mystery. The issue of whether calpain can act as a-secretase currently remains a theoretical dilemma. This dilemma, as well as other competing models, should be attractive in the future investigations. The issue is also crucial for an in-depth understanding of the structure-functional relationships of calpain and the mechanisms whereby many membrane-anchored proteins regulate a large number of biological processes. The quest may impact our current knowledge about the boundary of Ca2+ signaling by addressing the question of whether, and if so how, a calcium-dependent protease can function across the cell membrane.