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

2. INTRODUCTION

Alzheimer' disease (AD) is characterized by cerebral deposition of ß-amyloid protein (Aß) as senile plaques and accumulation of tau protein as neurofibrillary tangles (1-4). Aß is derived from its much larger precursor, ß-amyloid precursor protein (APP). Processing of APP in vivo occurs by two major pathways. APP can either be cleaved within its Aß domain at the Lys16 site by a putative a-secretase. In AD patients, APP is somehow excessively cleaved by ß/g-secretases leading to overproduction of Aß (1,2). While the mechanisms underlying this abnormality are not well understood, two possibilities appear to be most relevant: either a-secretase is "inactivated", or ß/g-secretases are "overactivated" in AD. Despite considerable experimental efforts devoted to this area, the identity of the secretases remains unknown (for reviews, see 3-6). This issue is of primary importance because Aß accumulation is among the earliest detectable histological lesions in the aging brain preceding the clinical manifestations of AD by decades. Although some other issues around amyloid lesions are also of interest (such as the mechanisms of Aß fibrillogenesis and its cell-damaging effects), it is apparent that these other events are secondary to Aß overproduction in AD progression.

In addition to protease abnormalities, an imbalance of intracellular calcium homeostasis is another salient defect in AD pathogenesis (though the direction of the imbalance is debatable)(8,9). Therefore, calcium-dependent proteases such as calpain should be expected to play a key role in the abnormal APP processing in AD by serving as a critical link between the protease abnormality and calcium imbalance. However, although the implication of calpain in long-term potentiation and tau degradation has begun to be elucidated (10,11), virtually nothing is definitively known about the roles of this protease in APP processing. In this context, it is necessary to further explore this important issue.