Pathology - Research Publications
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ItemNo Preview AvailableEffect of Metal Chelators on γ-Secretase Indicates That Calcium and Magnesium Ions Facilitate Cleavage of Alzheimer Amyloid Precursor Substrate.(Wiley, 2010-12-28)Gamma-secretase is involved in the production of Aβ amyloid peptides. It cleaves the transmembrane domain of the amyloid precursor protein (APP) at alternative sites to produce Aβ and the APP intracellular domain (AICD). Metal ions play an important role in Aβ aggregation and metabolism, thus metal chelators and ligands represent potential therapeutic agents for AD treatment. A direct effect of metal chelators on γ-secretase has not yet been investigated. The authors used an in vitro γ-secretase assay consisting of cleavage of APP C100-3XFLAG by endogenous γ-secretase from rodent brains and human neuroblastoma SH-SY5Y, and detected AICD production by western blotting. Adding metalloprotease inhibitors to the reaction showed that clioquinol, phosphoramidon, and zinc metalloprotease inhibitors had no significant effect on γ-secretase activity. In contrast, phenanthroline, EDTA, and EGTA markedly decreased γ-secretase activity that could be restored by adding back calcium and magnesium ions. Mg(2+) stabilized a 1,000 kDa presenilin 1 complex through blue native gel electrophoresis and size-exclusion chromatography. Data suggest that Ca(2+) and Mg(2+) stabilize γ-secretase and enhance its activity.
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ItemBACE Inhibition as a Therapeutic Strategy for Alzheimer’s Disease(Bentham Science eBooks, 2015-07-22)Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease and the most common cause of dementia. One of the characteristic hallmarks of AD brains upon post-mortem examination is the presence of amyloid plaques containing aggregates of the neurotoxic amyloid-β peptide Aβ. This peptide is produced from the amyloid precursor protein (APP) by proteolytic cleavage, firstly by BACE1 (β-site amyloid precursor protein cleaving enzyme 1 or β-secretase) and subsequently by γ-secretase. After Phase III, clinical trials of a γ-secretase inhibitor were abandoned due to adverse secondary effects, the focus has shifted to BACE1 as a key drug target in AD. Numerous BACE inhibitors have been produced, many of which have been shown in animal models to reduce the levels of Aβ in the brain. Intensive research effort for more than a decade has seen certain BACE1 inhibitors advance through human trials. Despite this progress, however, concerns that using BACE1 inhibition to reduce Aβ could cause unwanted side-effects (termed “mechanism-based toxicity”) have arisen as the list of BACE1 substrates continues to grow. In addition to APP, recent proteomics studies have identified novel BACE1 substrates, many of which have known roles in the developing and mature brain. This chapter aims to review the BACE inhibition strategy and describe the development of BACE inhibitors for AD therapy, highlighting both the promise and the potential pitfalls of this approach. The potential consequences of inhibiting BACE1 processing of these other BACE1 substrates along with APP will be discussed.
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ItemBACE inhibitors as potential therapeutics for Alzheimer's disease.(Bentham Science Publishers Ltd., 2007-11)Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Abeta production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.