Article

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

Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia.
Biological Chemistry (Impact Factor: 3.27). 08/2010; 391(8):849-59. DOI: 10.1515/BC.2010.089
Source: PubMed

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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    • "AlthoughtheproteolyticprocessingofAPPbyb-secretase canleadtothepathologicalproductionofAb,b-cleavageisa normalprocess.Generally,thecleavageoftransmembrane proteinsbyanADAMorBACE(ectodomainshedding)is commonlyinvolvedintheactivationofanumberof functionalpathways.EctodomainsheddingbyADAMsis essentialforthereleaseofmanycytokinesandgrowthfactor ligands,suchasepidermalgrowthfactor(EGF)(Blobel 2005).Additionally,ADAMsareinvolvedinectodomain sheddingofgrowth-factorreceptors,suchashumanepider- malgrowthfactorreceptor2(Liuetal.2006)andNotch (BozkulakandWeinmaster2009).Ectodomainsheddingby BACEisalsolikelytoberequiredfortheproperfunctionof anumberofproteins(Klaveretal.2010).Forexample, neureguliniscleavedbyBACE1andADAM17toreleasean ectodomainfragment,whichactsinaparacrinemannerto stimulatemyelination(Flecketal.2013).Therefore, cleavagebyADAMsorBACEcanpotentiallyfacilitate cellularsignallinginavarietyofways,eitherbyreleaseof growthfactorsorbyligand-dependentactivationofcellular receptors. RIPbyc-secretaseisalsoaprocessinvolvedinthenormal functionofmanyproteins.RIPcanservetwogeneral functions.First,itcanremovethemembrane-associated fragmentthatisproducedbyectodomainshedding.Second,it cancatalysetheproductionofintracellularsignallingdomains (Lichtenthaleretal.2011).c-Secretasehasover80currently "
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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 reviews studies on the structure, expression and post-translational processing of β-amyloid precursor protein (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.
    Full-text · Article · Feb 2014 · Journal of Neurochemistry
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    • "There have been some high profile failures of various drug candidates targeted at the formation or aggregation of Aβ in recent years [48]. Most notably, the development of inhibitors of β-secretase (β-amyloid cleaving enzyme-1 or BACE-1) has proved to be difficult because of inherent medicinal chemistry problems [49] and inhibitors of γ-secretase have resulted in undesirable side-effects, due to inhibition of Notch processing [50]. ‘Notch sparing’ γ-secretase inhibitors are in development, but could fail because of side effects due to the unavoidable accumulation of the toxic carboxyl-terminal fragment of APP (CTFβ) [50]. "
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    • "The worldwide increase of life expectancy and substantial increase in the number of patients with AD [4] makes it a serious public health problem [11]. "
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