Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions

Klaver, David W; Wilce, Matthew Charles James; Cui, Hao; Hung, Amos C.; Gasperini, Robert; Foa, Lisa; Small, David H.

doi:10.1515/bc.2010.089

Cited by 44 publications

(36 citation statements)

References 134 publications

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“…18 So far, decreasing APP and/or inhibiting BACE1 have been considered as targets for developing therapeutic strategy for AD. 18,19 Aβ 1À40 and Aβ 1À42 are major Aβ forms that occur in the brain tissue and circulation of AD patients, and they also play clinical significance for AD deterioration because both are insoluble and able to cause aggregation of amyloid plaques. 20,21 In our present study, the intake of test compounds lowered BACE1 activity and repressed the mRNA expression of APP and BACE1, which subsequently decreased available Aβ precursors and lowered Aβ formation.…”

Section: ' Discussionmentioning

confidence: 99%

s-Allyl Cysteine, s-Ethyl Cysteine, and s-Propyl Cysteine Alleviate β-Amyloid, Glycative, and Oxidative Injury in Brain of Mice Treated by d-Galactose

Tsai¹,

Chiu²,

Yang³

et al. 2011

J. Agric. Food Chem.

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The neuroprotective effects of s-allyl cysteine, s-ethyl cysteine, and s-propyl cysteine in D-galactose (DG)-treated mice were examined. DG treatment increased the formation of Aβ(1-40) and Aβ(1-42), enhanced mRNA expression of β-amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1), and reduced neprilysin expression in brain (P < 0.05); however, the intake of three test compounds significantly decreased the production of Aβ(1-40) and Aβ(1-42) and suppressed the expression of APP and BACE1 (P < 0.05). DG treatments declined brain protein kinase C (PKC) activity and mRNA expression (P < 0.05). Intake of test compounds significantly retained PKC activity, and the expression of PKC-α and PKC-γ (P < 0.05). DG treatments elevated brain activity and mRNA expression of aldose reductase (AR) and sorbitol dehydrogenase as well as increased brain levels of carboxymethyllysine (CML), pentosidine, sorbitol, and fructose (P < 0.05). Test compounds significantly lowered AR activity, AR expression, and CML and pentosidine levels (P < 0.05). DG treatments also significantly increased the formation of reactive oxygen species (ROS) and protein carbonyl and decreased the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (P < 0.05); however, the intake of test compounds in DG-treated mice significantly decreased ROS and protein carbonyl levels and restored brain GPX, SOD, and catalase activities (P < 0.05). These findings support that these compounds via their anti-Aβ, antiglycative, and antioxidative effects were potent agents against the progression of neurodegenerative disorders such as Alzheimer's disease.

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Section: ' Discussionmentioning

confidence: 99%

s-Allyl Cysteine, s-Ethyl Cysteine, and s-Propyl Cysteine Alleviate β-Amyloid, Glycative, and Oxidative Injury in Brain of Mice Treated by d-Galactose

Tsai¹,

Chiu²,

Yang³

et al. 2011

J. Agric. Food Chem.

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“…Additionally, ADAMs are involved in the ectodomain shedding of growth-factor receptors, such as human epidermal growth factor receptor 2 (70) and Notch (71). Ectodomain shedding by BACE is also likely to be required for the proper function of a number of proteins (72). For example, neuregulin-1 (NRG1) is cleaved by BACE1 and ADAM17 to release an ectodomain fragment that acts in a paracrine manner to stimulate myelination (73).…”

Section: App Processingmentioning

confidence: 99%

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Nguyen¹

2015

Biomolecular Concepts

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Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age < 65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age > 65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APPmRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

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“…Not shown Lichtenthaler et al (2003) Published BACE1 substrates and their possible functions as well as a link to the described phenotypes of BACE1 knockout mice is listed [modified from (Klaver et al 2010)] Exp Brain Res (2012) 217:331-341 337 mouse models and derived cell lines are extremely valuable tools that will allow more detailed studies of the multiple cellular roles of these proteases.…”

Section: Cell Adhesion and Inflammationmentioning

confidence: 99%

Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin

2011

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Alzheimer's disease causing mutations in the amyloid precursor protein (APP) or in the Presenilin 1 (PS1) or Presenilin 2 (PS2) genes increase the production of amyloid peptides (Aβ) that precipitate in amyloid plaques. Since amyloid plaques are also a prominent feature of sporadic Alzheimer's disease (AD), abnormal proteolysis of APP and the generation of amyloid beta (Aβ) are key events in the pathogenesis of AD. The proteases (secretases) that cleave APP are therefore important therapeutic targets, both for the rare familial forms but likely also for the sporadic forms of AD. The identification and understanding of the (neuro)biological functions of the α-, β-, and presenilin/γ-secretase (complexes) is important for the development of drugs and the delineation of their associated side effects. The potential impact of this type of research exceeds the AD field since the function of these secretases are also linked to cellular pathways like ectodomain shedding of growth factors and regulated intramembrane proteolysis of receptors in developmental biology, tissue homeostasis, and tumorigenesis. The generation of mice deficient in presenilin 1, presenilin 2, the α-secretase ADAM10, and the β-secretases BACE1 and BACE2 were instrumental for the elucidation of the physiological functions of these proteases. Using these mouse models understanding how these secretases regulate amyloid peptide formation and how they exert their diverse biological functions could be significantly increased. This review attempts to summarize selected aspects of the current view of the multiple roles such proteases play in health and disease.

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Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions

Cited by 44 publications

References 134 publications

s-Allyl Cysteine, s-Ethyl Cysteine, and s-Propyl Cysteine Alleviate β-Amyloid, Glycative, and Oxidative Injury in Brain of Mice Treated by d-Galactose

s-Allyl Cysteine, s-Ethyl Cysteine, and s-Propyl Cysteine Alleviate β-Amyloid, Glycative, and Oxidative Injury in Brain of Mice Treated by d-Galactose

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin

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