Please note these web pages are part of an assignment for a graduate course in Advanced Biochemistry and Molecular Biology (BCMB8010) at the University of Georgia. Questions should be directed to Crystal Jackson.

INTRODUCTION

b-Secretase: An Amyloid Precursor Protein Cleaving Enzyme and its Implications in Alzheimer's Disease Patients

b-amyloid or Ab (amyloid b-protein), 40-43 residues, is a neurotoxic peptide that is deposited in fibrillar form in senile plaques in the brains of Alzheimer's Disease (AD) patients. It is generated by proteolysis of several transmembrane glycoproteins known as Amyloid Precursor Protiens (APP), 100-140 kDa, and is located partly within the ectodomain and partly within the transmembrane domain of APP. The three primary enzymes involved in the release of the Ab are as follows: a-secretase, b-secretase and g-secretase [1]. a-Secretase cleaves APP during intracellular transport between Lys-687 and Leu-688 to yield nonamyloidogenic fragments. g-secretase, most likely localized in the endoplasmic reticulum (ER), releases the C-terminus of Ab and is most likely active in acidic compartments such as endosomes or lysosomes. The main focus of this report, however is the enzyme b-secretase. b-secretase cleaves the N-terminus of APP to yield the N-terminus of Ab. Recent studies have identified b-secretase as BACE (Beta-Site Amyloid Beta APP-Cleaving Enzyme), a unique member of the pepsin family of aspartyl proteases. BACE has an N-terminal catalytic domain containing two aspartate residues which is linked to a 17-residue transmembrane region and a short C-terminal cytoplasmic tail [2]. Expressed initially as a preprotein in the cell, BACE sub sequentially matures in the Golgi. Additionally, it contains four potential N-linked glycosylation sites and a propeptide sequence at the N-terminus. Because BACE is similar in structural homology to an HIV protease, certain HIV inhibitors are being tested on it. Furthermore, it is suspected that BACE has important physiological implications. Its transmembrane domain and unusual disulfide structures yield it as a prime target for AD treatment [3]. While it is certain that proteolytic cleavage of the amyloid protein from APP by APP secretases is a major occurrence in AD pathogenesis, the interrelations of the three main enzymes is still being explored.

This report will explain 1) the structure and function of APP secretases, particularly b-secretase, 2) characterization of several APP genes 3) expression and localization of APP secretases, and 5) the biological significance of APP secretases.

Acknowledgements: I extend my sincere thanks to Dr. Kelly Moremen, Dr. Robert Woods, and Dr. William York for their invaluable instruction throughout the course.