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Background

Alzheimer's Disease (AD) is one of the most common neurodegenerative diseases worldwide. Clinically, it is characterized by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles, which results in neuronal dysfunction and cell death. Central to this disease is the differential processing of the integral transmembrane glycoprotein Amyloid β (A4) precursor protein (APP) that exists as several isoforms. The amino acid sequence of APP contains the amyloid domain, which can be released by a two-step proteolytic cleavage. β-secretase (BACE) is an aspartic acid proteinase that catalyses the initial step in APP processing by cleaving and releasing a soluble, extracellular APP-β (sAPPβ) ectodomain and generating a membrane-bound, carboxy-terminal fragment consisting of 99 amino acids (CTF99). Additional processing of CTF99 by γ-secretase generates the amyloid β-peptide (Aβ) that forms aggregates in the brains of AD patients. BACE is an attractive target for inhibitors in AD therapy since it catalyses the first and rate limiting step in amyloidogenic APP processing. Pro-BACE-1 is synthesized in the ER before it is transported to the trans-Golgi network to undergo maturation.