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
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.
Available from: Edgar Dawkins
- "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.
Available from: David Allsop
- "There have been some high profile failures of various drug candidates targeted at the formation or aggregation of Aβ in recent years . 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  and inhibitors of γ-secretase have resulted in undesirable side-effects, due to inhibition of Notch processing . ‘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) . "
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ABSTRACT: Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH(2)) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001), all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer's disease.
Available from: Evandro Pizeta Semighini
- "The worldwide increase of life expectancy and substantial increase in the number of patients with AD  makes it a serious public health problem . "
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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.
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