Keywords
Beta-amyloid; Cathepsin B; Gene knockout; Amyloid precursor protein; Protease
Introduction
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that results in progressive loss of memory and accumulation of neurotoxic β-amyloid (Aβ) peptides in LY450139 [1], [2] and [3]. The abnormal accumulation of Aβ peptides has been demonstrated as a major factor in the disease, based largely on studies of transgenic mouse models which overproduce Aβ, resulting in memory deficit and amyloid plaque brain pathology similar to that observed in AD patients [4], [5] and [6]. Aβ peptides are generated from the amyloid precursor protein (APP) by proteases known as β- and γ-secretases, which release the N- and C-termini of Aβ, respectively. Several forms of Aβ are produced, including Aβ40 (1–40) and Aβ42 (1–42), which have the same N-termini but differ in their C-terminal residues.
The accumulation of brain Aβ can be reduced by inhibiting Aβ production, via reduction of β-secretase processing of APP. The vast majority of AD patients express wild-type (wt) APP (hAPPwt) which contains the wt β-secretase cleavage site sequence [7], [8] and [9]. The aspartyl protease BACE 1 is a β-secretase [10], [11], [12], [13] and [14], but it is relatively inefficient at cleaving the wt β-secretase site [15], [16] and [17]. Inhibitors of BACE 1 have not yet been shown to reduce brain Aβ or improve memory deficit in AD patients. Thus, there remains a need to identify other potential targets that may also reduce production of brain Aβ from APP [17] and [18].
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