Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ) is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE)-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.

Keywords: amyloid; aspartyl protease; dementia; neuregulin; secretase.

Figure 1

Disruption of the processing balance of the amyloid precursor protein (APP) in Alzheimer’s disease. The APP can be processed through two alternative pathways. In the α-secretase (α-sec) pathway (or nonamyloidogenic pathway), APP is cleaved by α-sec, which releases the soluble sAPPα N-terminal fragment, creating a membrane-tethered, C-terminal fragment of 83 amino acids (C83). α-Secretase (α-sec) cleavage occurs within the amyloid-β (Aβ) domain (shown in dark red) and precludes Aβ formation. C83 is further processed by γ-secretase (γ-sec) to produce the 3 kDa, nonamyloidogenic peptide p3 and release the APP intracellular domain (AICD, shown in light green) in the cytosol. In the β-secretase pathway (or amyloidogenic pathway), cleavage by β-site APP-cleaving enzyme (BACE1) releases the soluble APP N-terminal fragment (sAPPβ), which can be further processed by an unknown protease to liberate a fragment (shown in lilac) that can activate DR6 receptors. BACE1 cleavage of APP also produces the membrane-tethered C-terminal fragment of 99 amino acids (C99), which is the direct precursor to Aβ. Further processing of C99 by γ-sec achieves the release of Aβ in the extracellular or intravesicular space and AICD in the cytosol. When Aβ production reaches a threshold, the peptide self-aggregates to form toxic oligomers that trigger degeneration of neuronal cells by a mechanism that involves free radical formation and shifts the balance of APP processing towards the amyloidogenic pathway.

Figure 2

Schematic diagram of β-site amyloid precursor protein-cleaving enzyme (BACE)-1. BACE1 is translated as a precursor protein, with a signal peptide (SP) and a prosequence (Pro). The mature protein consists of a large enzymatic domain (in blue, with the two motifs that constitute the active site in yellow boxes; DTG stands for aspartyl-threonyl-glycyl and DSG for aspartyl-seryl-glycyl), a transmembrane domain (TM), and a short cytoplasmic domain (CD) containing an endosomal sorting sequence (white box; DISLL stands for aspartyl-isoleucyl-seryl-leucyl-leucyl). The four-leaf designs represent the N-glycosylation sites.

Figure 3

Published chemical structure of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in preclinical and clinical trials. The precise structure of Pfizer compound PF-05297909 has not been disclosed, but it is presumably derived from the general formula given in Brodney’s United States Patent and Trademark Office application 20110224231, where R1 and R1′ are each independently hydrogen, alkyl, or alkenyl, R2 is alkyl, cycloalkyl, or alkenyl, B is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and A is independently aryl, cycloalkyl, heterocycloalkyl, or heteroaryl.