Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Abstract

The β-site APP cleaving enzymes 1 and 2 (BACE1 and BACE2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein (APP). BACE1 is a major drug target for Alzheimer’s disease because BACE1-mediated cleavage of APP is the first step in the generation of the pathogenic amyloid-β peptides. BACE1, which is highly expressed in the nervous system, is also required for myelination by cleaving neuregulin 1. Several recent proteomic and in vivo studies usingBACE1-andBACE2-deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE1 this includes axon guidance, neurogenesis, muscle spindle formation, and neuronal network functions, whereas BACE2 was shown to be involved in pigmentation and pancreatic β-cell function. This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer’s disease.

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

“…It is marked by the generation and deposition of small, neurotoxic Aβ peptides in form of oligomeric aggregates and finally plaques in the brain parenchyma and vasculature. The Aβ peptide results from the sequential proteolytic processing of the amyloid precursor protein (APP) by β‐ and γ‐secretases (Lichtenthaler et al ., 2011; Vassar et al ., 2014). …”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…3,4 The latter mainly consist of aggregated Ab peptides, which are generated from the amyloid precursor protein (APP) in a proteolytic cascade. 5 Once considered the evil moiety, amyloid plaques are now rather seen as inert deposits. Instead, oligomeric assemblies of Ab have been identified as the neurotoxic substrate.…”

“…Sequential cleavage of APP by BACE1 and the g-secretase complex creates Ab moieties, which are prone to aggregation. 5 Competitively, a-secretase cleaves APP instead of BACE1 and directs proteolysis toward the non-amyloidogenic pathway with shorter metabolites. Interdependence with further APP-cleaving secretases, i.e.…”

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

“…It has been observed that knock-out of BACE1 or administration of the BACE1 inhibitor dramatically decreases A␤ levels in the brain and attenuates behavioral and electrophysiological deficits in APP-transgenic mice (4 -6). Thus, extensive investigations have focused on the direct inhibition of BACE1 to reduce A␤ load in the AD brain; however, these studies have unfortunately not yet led to any efficacious therapy for AD patients due to the various physiological roles of BACE1 (7). Using alternative methods to inhibit BACE1 might be a preferable investigative approach.…”