The sources of information in this Review were mainly peer-reviewed primary research journal articles and secondary review articles that were identified on PubMed with the search terms “beta-secretase and Alzheimer's disease”, “BACE and Alzheimer's disease”, “BACE inhibitor”, and “BACE inhibitor clinical trial” from Jan 1, 1990, to Oct 24, 2013. In a few instances, information about the status of BACE1 inhibitor clinical trials was obtained from statements on company websites. Criteria used to
ReviewTargeting the β secretase BACE1 for Alzheimer's disease therapy
Introduction
Alzheimer's disease is characterised by the cerebral accumulation of extracellular deposits called amyloid plaques that are composed of amyloid β peptides (Aβ) of 38–43 aminoacids. Amyloid β plaques are cardinal histopathological hallmarks of Alzheimer's disease, fundamental to the amyloid cascade hypothesis of the disease, which posits cerebral Aβ accumulation as a crucial early player in disease pathogenesis, ultimately leading to neurodegeneration and dementia.1 If the amyloid hypothesis is correct, then inhibition of cerebral Aβ accumulation could benefit patients with Alzheimer's disease.
The β secretase, referred to as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), is the enzyme that initiates Aβ production by cleaving the extracellular domain of APP. Inhibitors of BACE1 are being considered at present for their potential to lower cerebral Aβ concentrations and to treat and prevent Alzheimer's disease. Although several promising BACE1 inhibitors are being tested in human clinical trials, many questions remain about the safety of these drugs, the optimum level of BACE1 inhibition to achieve efficacy without unacceptable side-effects, and the stage of disease at which to treat for greatest therapeutic gain. Here, we review the potential of therapeutic BACE1 inhibition for Alzheimer's disease at a crucial time in the search for effective approaches to treatment and prevention.
Section snippets
Amyloid β and Alzheimer's disease
In the brain, Aβ is predominantly produced by neurons, although other cell types, including astrocytes and other glia, also generate Aβ especially under stress conditions that induce glial activation, as occurs in Alzheimer's disease. Aβ is formed by the sequential proteolysis of the type 1 membrane protein APP (figure 1A). APP is first cleaved by the β-secretase enzyme to yield a membrane-bound C-terminal fragment called C99.2 A second enzyme named γ secretase, composed of four transmembrane
BACE1
In view of the role of Aβ in Alzheimer's disease pathogenesis, the molecular cloning of the secretase enzymes became a major goal for their value as drug targets. The characteristics of Aβ production and secretase activities in cultured cells allowed the development of cell-based assays for secretase identification. Five groups independently reported the molecular cloning of the β-secretase enzyme, variously named β-site APP cleaving enzyme (BACE), Asp2, and memapsin 2.12, 13, 14, 15, 16
BACE1 knockout mice
To unequivocally show in vivo that BACE1 is the β secretase implicated in Alzheimer's disease, several groups used gene targeting strategies to generate BACE1 knockout (−/−) mice.24, 25, 26, 27 These mice were initially reported to be viable and fertile with no overt phenotype, and to have normal gross morphology and behaviour, tissue histology, and blood cell and clinical chemistry characteristics, implying that therapeutic inhibition of BACE1 might be free of mechanism-based side-effects. The
BACE1 inhibitor drugs for Alzheimer's disease
In view of the strong in-vivo and in-vitro validation of BACE1 as the major β-secretase enzyme in the brain, intense efforts are underway in both academia and industry to develop small-molecule inhibitors of BACE1. Initial inhibitors were non-cleavable peptide-based transition state analogues modelled after the β-secretase cleavage site of APP.14, 60 In vitro, these sizable peptidomimetic molecules are potent BACE1 inhibitors, mainly because the large open BACE1 active site evolved to bind
Outstanding questions
The long-awaited initiation of clinical trials for BACE1 inhibitors is a promising development and raises hopes that disease-modifying therapies involving BACE1 inhibition for Alzheimer's disease are within reach. However, several crucial questions concerning therapeutic goals and outcomes of these trials remain.
Conclusions and future developments
As the enzyme that initiates Aβ production, BACE1 is a key therapeutic target for Alzheimer's disease. The Ala673Thr mutation and BACE1 gene knockout reduce Aβ generation, strongly suggesting that BACE1 inhibition should prove effective for Alzheimer's disease. Although BACE1−/− mice are viable and fertile, they display many complex neurological phenotypes (table 1), which imply that BACE1 inhibitor drugs could cause mechanism-based side-effects, such as hypomyelination, seizures, axon guidance
Search strategy and selection criteria
References (85)
- et al.
ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function
Neuron
(2013) - et al.
Identification of a novel aspartic protease (Asp 2) as beta-secretase
Mol Cell Neurosci
(1999) - et al.
Expression analysis of BACE2 in brain and peripheral tissues
J Biol Chem
(2000) - et al.
BACE2 functions as an alternative alpha-secretase in cells
J Biol Chem
(2001) - et al.
Antagonistic effects of beta-site amyloid precursor protein-cleaving enzymes 1 and 2 on beta-amyloid peptide production in cells
J Biol Chem
(2003) - et al.
Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice
J Biol Chem
(2005) - et al.
BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease
Neuron
(2004) - et al.
BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time
Neurobiol Dis
(2003) - et al.
BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
Neurobiol Dis
(2007) - et al.
Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice
J Biol Chem
(2007)
Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme 1
J Biol Chem
β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects
J Biol Chem
BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease
Neurobiol Aging
BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes
Mol Cell Neurosci
BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway
Cell Rep
Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass
Cell Metab
The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo
J Biol Chem
Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination
J Biol Chem
Abnormal axonal guidance and brain anatomy in mouse mutants for the cell recognition molecules close homolog of L1 and NgCAM-related cell adhesion molecule
Neuroscience
The canonical Notch signaling pathway: unfolding the activation mechanism
Cell
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
Science
The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential
J Neurosci
gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?
Nat Rev Neurosci
The secretases: enzymes with therapeutic potential in Alzheimer disease
Nat Rev Neurol
The LDL receptor
Arterioscler Thromb Vasc Biol
The genetics of Alzheimer disease
Cold Spring Harb Perspect Med
A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid
Nat Genet
A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis
Science
ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons
EMBO J
A mutation in APP protects against Alzheimer's disease and age-related cognitive decline
Nature
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
Science
Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity
Nature
Purification and cloning of amyloid precursor protein beta-secretase from human brain
Nature
Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein
Proc Natl Acad Sci USA
Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons
EMBO J
BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions
J Neurosci
BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein
Proc Natl Acad Sci USA
A non-amyloidogenic function of BACE-2 in the secretory pathway
J Neurochem
Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation
Nat Neurosci
BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics
Hum Mol Genet
BACE1 is the major beta-secretase for generation of Abeta peptides by neurons
Nat Neurosci
The Alzheimer's β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques
Acta Neuropathol
Cited by (523)
Artificial intelligence for drug discovery and development in Alzheimer's disease
2024, Current Opinion in Structural BiologyEffect of salidroside on neuroprotection and psychiatric sequelae during the COVID-19 pandemic: A review
2024, Biomedicine and PharmacotherapyDiscovery of novel multifunctional ligands targeting GABA transporters, butyrylcholinesterase, β-secretase, and amyloid β aggregation as potential treatment of Alzheimer's disease
2023, European Journal of Medicinal Chemistry