Discovery of the Cysteine Protease Cathepsin B as a Drug Target for Alzheimer's Disease
Protease enzymes represent logical drug targets in human diseases. Alzheimer's disease (AD) is a devastating neurodegenerative disease resulting in severe loss of memory during advanced aging. Development of AD involves the accumulation of neurotoxic β-amyloid (Aβ) peptides in brains of AD patients, which represents a primary factor in the progressive memory loss observed in animal models of AD. Beta-amyloid peptides are produced by proteases that cleave the amyloid precursor protein (APP) at the β- and γ-secretase sites of APP flanking the N- and C-termini of β-amyloid peptide sequences, respectively, to generate Aβ(1–40) and Aβ(1–42). The strategy to identify and inhibit the protease(s) cleaving at the β-secretase site can reduce production of both forms of Aβ peptides. The majority of AD patients express APP with the normal wild-type β-secretase site, and a few patients express APP with the Swedish mutation at the β-secretase site. The search for proteolytic activity that cleaves the wild-type β-secretase site led to identification of cathepsin B that produces Aβ in regulated secretory vesicles which provide a major portion of extracellular Aβ. Inhibitors of cathepsin B effectively reduce brain Aβ and improve memory in mouse models expressing human APP with the wild-type β-secretase site, but not in mice expressing APP with the Swedish mutant β-secretase site. The specificity of cathepsin B for cleaving the wild-type β-secretase site, but not the Swedish mutant site, provides the basis for the pharmacogenetic differences in drug responses in the two different genetic AD animal models. In contrast to cathepsin B, the BACE1 β-secretase prefers to cleave the Swedish mutant site. Discussion of BACE1 data in the field indicates that they do not preclude cathepsin B as another β-secretase. Cathepsin B and BACE1 may participate jointly as β-secretases. Significantly, the majority of AD patients express WT APP, and therefore, inhibitors of cathepsin B represent candidate drugs for AD.