更新于：2024-11-01

γ-secretase x CTSB

更新于：2024-11-01

基本信息

关联

项与 γ-secretase x CTSB 相关的药物

Begacestat

靶点

CTSB x γ-secretase

作用机制

CTSB抑制剂 [+1]

在研机构-

原研机构

Pfizer Inc.

在研适应症-

非在研适应症

阿尔茨海默症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 γ-secretase x CTSB 相关的临床试验

NCT00959881 / Completed临床1期

Combined Administration Of Begacestat And Donepezil: A Multiple-Dose Study In Healthy Subjects

This study examines the cardiac effects (effects on the heart) of administering donepezil and begacestat together to healthy subjects.

开始日期2009-08-01

申办/合作机构

Wyeth AB

[+1]

NCT00547560 / Completed临床1期

An Ascending Multiple Dose Study Of The Safety, Pharmacokinetics, And Pharmacodynamics Of GSI-953 Administered Orally To Healthy Elderly Subjects

To assess the safety and tolerability of ascending, multiple, oral doses of GSI-953 in healthy elderly subjects.

开始日期2007-08-01

申办/合作机构

Wyeth AB

[+1]

100 项与 γ-secretase x CTSB 相关的临床结果

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100 项与 γ-secretase x CTSB 相关的转化医学

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0 项与 γ-secretase x CTSB 相关的专利（医药）

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项与 γ-secretase x CTSB 相关的文献（医药）

2024-01-01·eneuro

Negative Regulation of Cathepsins by β-Amyloid

Article

作者: Comby, Anne-Claire ; Lundin, Brianna ; Berezovska, Oksana ; Maesako, Masato

Genome wide association study (GWAS) uncovered Alzheimer's disease (AD) risk genes linked to the endo-lysosomal pathway. This pathway seems to be the gateway of protein aggregates, such as tau and α-synuclein, to the cytoplasm. Furthermore, we and others reported that the amyloid precursor protein (APP) C99 is predominantly processed by γ-secretase in the endo-lysosomal compartments, and β-amyloid (Aβ) peptides are enriched in the same subcellular loci. While the role(s) of APP/Aβ in the endo-lysosomal pathway has not been fully established, a recent study reported that Aβ, in particular Aβ42, inhibits cathepsin D (CTSD) activity. Here, we show using a cell-free in vitro assay that Aβ42 also blocks cathepsin B (CTSB) activity. Furthermore, we uncovered that the autocatalytic processing (i.e., conversion of single chain to heavy/light chains) of CTSB and CTSD is accelerated in APP-deficient cells compared with wild-type controls. Taken together, our findings further support the negative regulation of cathepsins by Aβ.

2022-02-01·Cellular and Molecular Life Sciences

Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing

Review

作者: da Cruz E Silva, Odete A B ; Vitória, José J M ; Trigo, Diogo

Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the accumulation of the β-amyloid peptide (Aβ) in the brain, along with profound alterations in phosphorylation-related events and regulatory pathways. The production of the neurotoxic Aβ peptide via amyloid precursor protein (APP) proteolysis is a crucial step in AD development. APP is highly expressed in the brain and is complexly metabolized by a series of sequential secretases, commonly denoted the α-, β-, and γ-cleavages. The toxicity of resulting fragments is a direct consequence of the first cleaving event. β-secretase (BACE1) induces amyloidogenic cleavages, while α-secretases (ADAM10 and ADAM17) result in less pathological peptides. Hence this first cleavage event is a prime therapeutic target for preventing or reverting initial biochemical events involved in AD. The subsequent cleavage by γ-secretase has a reduced impact on Aβ formation but affects the peptides' aggregating capacity. An array of therapeutic strategies are being explored, among them targeting Retinoic Acid (RA) signalling, which has long been associated with neuronal health. Additionally, several studies have described altered RA levels in AD patients, reinforcing RA Receptor (RAR) signalling as a promising therapeutic strategy. In this review we provide a holistic approach focussing on the effects of isoform-specific RAR modulation with respect to APP secretases and discuss its advantages and drawbacks in subcellular AD related events.

2018-06-01·Molecular Neurobiology2区 · 医学

Inhibition of Poly(ADP-ribose) Polymerase-1 Enhances Gene Expression of Selected Sirtuins and APP Cleaving Enzymes in Amyloid Beta Cytotoxicity

2区 · 医学

Article

作者: Lukiw, Walter J ; Strosznajder, Robert Piotr ; Strosznajder, Joanna B ; Wencel, Przemysław L

Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture. Moreover, the effect of endogenously liberated Aβ peptides in PC12 cells stably transfected with human gene for APP wild-type (APPwt) was analyzed. Our results demonstrated that AβO enhanced transcription of presenilins (Psen1 and Psen2), the crucial subunits of γ-secretase. Aβ peptides in APPwt cells activated expression of β-secretase (Bace1), Psen1, Psen2, and Parp1. The inhibitor of PARP1, PJ-34 in the presence of AβO upregulated transcription of α-secretase (Adam10), Psen1, and Psen2, but also Bace1. Concomitantly, PJ-34 enhanced mRNA level of nuclear Sirt1, Sirt6, mitochondrial Sirt4, and Parp3 in PC12 cells subjected to AβOs toxicity. Our data indicated that Aβ peptides through modulation of APP secretases may lead to a vicious metabolic circle, which could be responsible for maintaining Aβ at high level. PARP1 inhibition, besides activation of nuclear SIRTs and mitochondrial Sirt4 expression, enhanced transcription of enzyme(s) involved in βAPP metabolism, and this effect should be considered in its application against Aβ peptide toxicity.