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: 1.78). 01/2010; 3(6):618-28.
Source: PubMed

ABSTRACT 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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    • "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; DOI:10.1016/j.ejphar.2013.11.012 · 2.68 Impact Factor
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    • "The number of identified protein substrates for Bace proteases is steadily increasing, suggesting their involvement in multiple biological processes (Luo and Yan 2010; Kandalepas and Vassar 2012). Thus, it is very important to analyze potential effects of pharmacological inhibition of Bace proteases in order assess the safety and specificity of compounds designed for AD therapy. "
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    ABSTRACT: Read the full article 'Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes' on doi: 10.1111/jnc.12198.
    Journal of Neurochemistry 03/2013; 127(4). DOI:10.1111/jnc.12200 · 4.24 Impact Factor
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    • "Synaptic plasticity is a fundamental property of the brain and is likely responsible for its ability to carry out many important biological functions, including cognitive activity (Luo and Yan, 2010). Synapses undergo constant plastic changes in response to internal and environmental stimuli (Zhang and Poo, 2010). "
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    ABSTRACT: The brain is capable of remarkable synaptic reorganization following stress and injury, often using the same molecular machinery that governs neurodevelopment. This form of plasticity is crucial for restoring and maintaining network function. However, neurodegeneration and subsequent reorganization can also play a role in disease pathogenesis, as is seen in temporal lobe epilepsy and Alzheimer's disease. β-Secretase-1 (BACE1) is a protease known for cleaving β-amyloid precursor protein into β-amyloid (Aβ), a major constituent in amyloid plaques. Emerging evidence suggests that BACE1 is also involved with synaptic plasticity and nerve regeneration. Here we examined whether BACE1 immunoreactivity (IR) was altered in pilocarpine-induced epileptic CD1 mice in a manner consistent with the synaptic reorganization seen during epileptogenesis. BACE1-IR increased in the CA3 mossy fiber field and dentate inner molecular layer in pilocarpine-induced epileptic mice, relative to controls (saline-treated mice and mice 24-48 h after pilocarpine-status), and paralleled aberrant expression of neuropeptide Y. Regionally increased BACE1-IR also occurred in neuropil in hippocampal area CA1 and in subregions of the amygdala and temporal cortex in epileptic mice, colocalizing with increased IR for growth associated protein 43 (GAP43) and polysialylated-neural cell adhesion molecule (PSA-NCAM), but reduced IR for microtubule-associated protein 2 (MAP2). These findings suggest that BACE1 is involved in aberrant limbic axonal sprouting in a model of temporal lobe epilepsy, warranting further investigation into the role of BACE1 in physiological vs. pathological neuronal plasticity.
    Experimental Neurology 01/2012; 235(1):228-37. DOI:10.1016/j.expneurol.2012.01.003 · 4.62 Impact Factor
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