Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
ABSTRACT Alzheimer's disease (AD) is characterized by the extracellular deposition of the beta-amyloid protein (Abeta). Abeta is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by beta-secretase and gamma-secretase liberates Abeta from APP. The aspartyl protease BACE1 (beta-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Abeta, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.
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ABSTRACT: The β-amyloid precursor protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) of Alzheimer's disease. However, the normal function of APP remains largely unknown. This article reviews studies on the structure, expression and post-translational processing of APP, as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 02/2014; DOI:10.1111/jnc.12675 · 4.24 Impact Factor
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ABSTRACT: Alzheimer's Disease (AD) is the major cause of senile dementia, flawing out 10% of 65 years old population and 50% of 85 years old, globally. The major physiopathology of AD is the deposition of extracellular neuritic plaques in memory related areas of the brain. These plaques are composed of the -amyloid peptide resulting from the amyloi-dogenic pathway, that starts with the -secretase enzyme. BACE-1 (-secretase 1) is considered one of the most promising treatments of the disease. In this work, different molecular modeling and drug design techniques were used to design novel inhibitors of BACE-1, starting from structures available in the Protein Data Bank. The results obtained from virtual screening of compound libraries lead to 28 promising compounds, which were then evaluated by toxicity prediction, pharmacokinetic properties and analysis of the binding modes in the catalytic site, resulting in 10 compounds with high theoretical inhibition potential.Current Bioactive Compounds 03/2013; 9(1):14-20. DOI:10.2174/1573407211309010003
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ABSTRACT: β-Secretase (BACE1) is a major drug target for combating Alzheimer's disease (AD). Here we show that BACE1(-/-) mice develop significant retinal pathology including retinal thinning, apoptosis, reduced retinal vascular density and an increase in the age pigment, lipofuscin. BACE1 expression is highest in the neural retina while BACE2 was greatest in the retinal pigment epithelium (RPE)/choroid. Pigment epithelial-derived factor, a known regulator of γ-secretase, inhibits vascular endothelial growth factor (VEGF)-induced in vitro and in vivo angiogenesis and this is abolished by BACE1 inhibition. Moreover, intravitreal administration of BACE1 inhibitor or BACE1 small interfering RNA (siRNA) increases choroidal neovascularization in mice. BACE1 induces ectodomain shedding of vascular endothelial growth factor receptor 1 (VEGFR1) which is a prerequisite for γ-secretase release of a 100 kDa intracellular domain. The increase in lipofuscin following BACE1 inhibition and RNAI knockdown is associated with lysosomal perturbations. Taken together, our data show that BACE1 plays a critical role in retinal homeostasis and that the use of BACE inhibitors for AD should be viewed with extreme caution as they could lead to retinal pathology and exacerbate conditions such as age-related macular degeneration.EMBO Molecular Medicine 09/2012; 4(9):980-91. DOI:10.1002/emmm.201101084 · 8.25 Impact Factor