ABSTRACT
Alzheimer’s disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries. The risk of AD increases dramatically in individuals above the age of 70, and it is predicted that the incidence of AD will augment three fold within the next 50 years. AD can be classified into two forms: sporadic AD, which accounts for the vast majority of cases, and a rare familial form of AD (FAD), in which gene mutations have been identified. Cortical regions involved in learning and memory processes are reduced in size in AD patients as a result of degeneration of synapses and death of neurons.1 The pathological hallmarks of AD include intraneuronal neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, and deposition of β-amyloid plaques (Aβ) in the extracellular space. The pathological diagnosis of AD is dependent on the detection of neurofibrillary pathology in the form of NFT or neuritic plaques.2,3
Central to the disease is an altered proteolytic processing of the amyloid precursor protein (APP), resulting in overproduction and aggregation of neurotoxic forms of Aβ. APP is an integral membrane protein with a single, membrane-spanning domain; a large, extracellular N-terminus; and a shorter, cytoplasmic C-terminus. Aβ
is generated from the sequential cleavage of APP: a C-terminal membrane-bound fragment of 99 (C99, βCTFs) is produced by the β-secretase cleavage of APP, which is subsequently cleaved within the transmembrane domain4 (Figure 14.1 Panel A). BACE-1 was identified as the β-secretase that cleaves APP within the ectodomain.5-9 BACE-1 is expressed in all tissues, with the highest level of expression in the brain. BACE-1 is an intracellular type I transmembrane protein detected in the trans-Golgi network and endosomes.7 The role of BACE-1 in the generation of Aβ peptides was confirmed by the absence of Aβ peptides in mice with homozygous deletion of BACE-110 (Figure 14.1 Panel B).
