Inhibition of BACE1 for therapeutic usein Alzheimer's disease

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
International journal of clinical and experimental pathology (Impact Factor: 1.89). 01/2010; 3(6):618-28.
Source: PubMed


Since BACE1 was reported as the beta-secretase in Alzheimer's disease (AD) over ten years ago, encouraging progress has been made toward understanding the cellular functions of BACE1. Genetic studies have further confirmed that BACE1 is essential for processing amyloid precursor protein (APP) at the beta-secretase site. Only after this cleavage can the membrane-bound APP C-terminal fragment be subsequently cleaved by gamma-secretase to release so-called AD-causing Abeta peptides. Hence, in the past decade, a wide variety of BACE1 inhibitors have been developed for AD therapy. This review will summarize the major historical events during the evolution of BACE1 inhibitors designed through different strategies of drug discovery. Although BACE1 inhibitors are expected to be safe in general, careful titration of drug dosage to avoid undesirable side effects in BACE1-directed AD therapy is also emphasized.

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    • "Many substrate-based peptidomimetic inhibitors are developed by academic research groups and pharmaceutical companies. The problem with the BACE1 inhibitors P10-P4′, OM99-2 and OM00-3, is that they do not have the qualified drug properties: they are either too large in size, have a too short half-life in vivo, are not capable of passing the BBB or have low oral availability (Luo and Yan, 2010). Therefore, later generations of BACE1 inhibitors are smaller and often non-peptidic. "
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    ABSTRACT: Alzheimer's disease (AD) and vascular dementia are responsible for up to 90% of dementia cases. According to the World Health Organization (WHO), a staggering number of 35.6 million people are currently diagnosed with dementia. Blocking disease progression or preventing AD altogether is desirable for both social and economic reasons and recently focus has shifted to a new and promising drug: the β-secretase inhibitor. Much of AD research has investigated the amyloid cascade hypothesis, which postulates that AD is caused by changes in amyloid beta (Aβ) stability and aggregation. Blocking Aβ production by inhibiting the first protease required for its generation, β-secretase/BACE1, may be the next step in blocking AD progression. In April 2012, promising phase I data on inhibitor MK-8931 was presented. This drug reduced Aβ cerebral spinal fluids (CSF) levels up to 92% and was well tolerated by patients. In March 2013 data was added from a one week trial in 32 mild to moderate AD patients, showing CSF Aβ levels decreased up to 84%. However, β-site APP cleaving enzyme 1 (BACE1) inhibitors require further research. First, greatly reducing Aβ levels through BACE1 inhibition may have harmful side effects. Second, BACE1 inhibitors have yet to pass clinical trial phase II/III and no data on possible side effects on AD patients are available. And third, there remains doubt about the clinical efficacy of BACE1 inhibitors. In moderate AD patients, Aβ plaques have already been formed. BACE1 inhibitors prevent production of new Aβ plaques, but hypothetically do not influence already existing Aβ peptides. Therefore, BACE1 inhibitors are potentially better at preventing AD instead of having therapeutic use.
    Frontiers in Aging Neuroscience 07/2014; 6:165. DOI:10.3389/fnagi.2014.00165 · 4.00 Impact Factor
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    • "The orally administered compound CTS21166 (CoMentis) has so far been shown to be well tolerated and reduces plasma Aβ levels in healthy individuals in Phase I clinical trials (Tang, 2009). CoMentis is currently conducting a more thorough clinical evaluation of CT21166 in partnership with Astellas Pharma, Japan (Luo and Yan, 2010). Several γ-secretase inhibitors have reached Phase II and III clinical testing: semagacestat (LY-450139, Eli Lilly), tarenflurbil (Myriad Genetics), MK-0752 (Merck), E-2012 (Eisai), begacestat (GSI-953, Wyeth Research), only to be halted due to various hematological and gastrointestinal toxicity, viral and bacterial infections and skin reactions, most likely due to disruption of Notch function (Extance, 2010; Imbimbo, 2009; Mangialasche et al., 2010). "
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    ABSTRACT: Calcium ions are versatile and universal biological signaling factors that regulate numerous cellular processes ranging from cell fertilization, to neuronal plasticity that underlies learning and memory, to cell death. For these functions to be properly executed, calcium signaling requires precise regulation, and failure of this regulation may tip the scales from a signal for life to a signal for death. Disruptions in calcium channel function can generate complex multi-system disorders collectively referred to as "calciumopathies" that can target essentially any cell type or organ. In this review, we focus on the multifaceted involvement of calcium signaling in the pathophysiology of Alzheimer's disease, and summarize the various therapeutic options currently available to combat this disease. Detailing the series of disappointing AD clinical trial results on cognitive outcomes, we emphasize the urgency to design alternative therapeutic strategies if synaptic and memory functions are to be preserved. One such approach is to target early calcium channelopathies centrally linked to AD pathogenesis.
    European journal of pharmacology 12/2013; 739. DOI:10.1016/j.ejphar.2013.11.012 · 2.53 Impact Factor
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    • "5, 6, 7 As a proof of concept for this view, it has been demonstrated that BACE1 gene deletion (BACE1−/−) prevents the development of AD-like pathologies and memory impairments in different lines of amyloid precursor protein (APP) transgenic mice.8, 9, 10, 11 However, as BACE1 has a large catalytic site, it has been challenging to find small-molecule BACE1 inhibitors that can efficiently cross the blood–brain barrier and are large enough to block the substrate-binding site of this enzyme.12, 13, 14 Nevertheless, a recent progress in medicinal chemistry has led to the development of some promising nonpeptidomimetic BACE1 inhibitors that are reported to lower cerebral Aβ levels after systemic administration in various species such as mice, rats, monkeys and humans.15, 16, 17, 18, 19, 20, 21 "
    L Devi · M Ohno ·
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    ABSTRACT: The β-secretase enzyme BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which initiates amyloid-β (Aβ) production, is an excellent therapeutic target for Alzheimer's disease (AD). However, recent evidence raises concern that BACE1-inhibiting approaches may encounter dramatic declines in their abilities to ameliorate AD-like pathology and memory deficits during disease progression. Here, we used BACE1 haploinsufficiency as a therapeutic relevant model to evaluate the efficacy of partial inhibition of this enzyme. Specifically, we crossed BACE1(+/-) mice with 5XFAD transgenic mice and investigated the mechanisms by which Aβ accumulation and related memory impairments become less sensitive to rescue by BACE1(+/-) reduction. Haploinsufficiency lowered BACE1 expression by ∼50% in 5XFAD mice regardless of age in concordance with reduction in gene copy number. However, profound Aβ plaque pathology and memory deficits concomitant with BACE1 equivalent to wild-type control levels remained in BACE1(+/-)·5XFAD mice with advanced age (15-18 months old). Therefore, BACE1 haploinsufficiency is not sufficient to block the elevation of BACE1 expression (approximately twofold), which is also reported to occur during human AD progression, in 5XFAD mice. Our investigation revealed that PERK (PKR-endoplasmic reticulum-related kinase)-dependent activation of eIF2α (eukaryotic translation initiation factor-2α) accounts for the persistent BACE1 upregulation in BACE1(+/-)·5XFAD mouse brains at 15-18 months of age. Moreover, BACE1 haploinsufficiency was also no longer able to prevent reduction in the expression of neprilysin, a crucial Aβ-degrading enzyme, in 5XFAD mice with advanced age. These findings demonstrate that partial BACE1 suppression cannot attenuate deleterious BACE1-elevating or neprilysin-reducing mechanisms, limiting its capabilities to reduce cerebral Aβ accumulation and rescue memory defects during the course of AD development.
    Translational Psychiatry 07/2013; 3(7):e284. DOI:10.1038/tp.2013.59 · 5.62 Impact Factor
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