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The ?-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-? reduction to downstream disease-relevant effects.

ABSTRACT: Inhibition of ?-secretase 1 (BACE-1; also known as ?-site amyloid precursor protein-cleaving enzyme-1) is a current approach to fight the amyloid-? (A?) deposition in the brains of patients with Alzheimer's disease, and a number of BACE-1 inhibitors are being tested in clinical trials. The BACE-1 inhibitor NB-360, although not a clinical compound, turned out to be a valuable pharmacological tool to investigate the effects of BACE-1 inhibition on the deposition of different A? species in amyloid precursor protein (APP) transgenic mice. Furthermore, chronic animal studies with NB-360 revealed relationships between BACE-1 inhibition, A? deposition, and A?-related downstream effects on neuroinflammation, neuronal function, and markers of neurodegeneration. NB-360 effects on the processing of physiological BACE-1 substrates as well as on nonenzymatic BACE-1 functions have been investigated, complementing studies in BACE-1 knockout mice. Because NB-360 is also an inhibitor for BACE-2, nonclinical studies in adult animals revealed physiological effects of BACE-2 inhibition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

SUBMITTER: Neumann U

PROVIDER: S-EPMC6715607 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The β-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-β reduction to downstream disease-relevant effects.

Neumann Ulf U Machauer Rainer R Shimshek Derya R DR

British journal of pharmacology 20190310 18

Inhibition of β-secretase 1 (BACE-1; also known as β-site amyloid precursor protein-cleaving enzyme-1) is a current approach to fight the amyloid-β (Aβ) deposition in the brains of patients with Alzheimer's disease, and a number of BACE-1 inhibitors are being tested in clinical trials. The BACE-1 inhibitor NB-360, although not a clinical compound, turned out to be a valuable pharmacological tool to investigate the effects of BACE-1 inhibition on the deposition of different Aβ species in amyloid ...[more]

PMID: 30657591

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC. Pancreatic ductal adenocarcinoma xenografts were grown in Athymic Nude-Foxn1nu mice. RNA was extracted and profiled in Affymetrix platform to identify genes correlating with sensitivity to MRK-003

Project description:Positron emission tomography (PET) used for visualizing amyloid-? (A?) pathology has become an important tool for specific clinical diagnosis of Alzheimer's disease (AD). However, all available amyloid PET radioligands, such as [11C]PiB, reflect levels of insoluble A? plaques, but do not capture soluble and protofibrillar A? forms. When measured with current PET ligands, the plaque load appears to be fairly static during clinical stages of AD, and may not be affected by A? reducing treatments. The aim of the present study was to investigate if a novel PET radioligand, based on an antibody directed towards soluble aggregates of A?, could be used to detect changes in A? levels during disease progression and after treatment with a ?-secretase (BACE-1) inhibitor. Methods: One set of transgenic mice (tg-ArcSwe, model of A? pathology) aged between 7 and 16 months were PET scanned with the A? protofibril selective radioligand [124I]RmAb158-scFv8D3 to follow progression of A? pathology in the brain. A second set of tg-ArcSwe mice, aged 10 months, were treated with BACE-1 inhibitor NB-360 for 3 months and compared to an untreated control group. A set of 10 months old tg-ArcSwe mice also underwent PET scanning, acting as a baseline group. Brain tissue was isolated after PET to determine levels of A? by ELISA and immunohistochemistry. Results: Concentration of [124I]RmAb158-scFv8D3 in tg-ArcSwe mice, measured in vivo with PET, increased with age and corresponded well with ex vivo autoradiography and A? immunohistochemistry. Tg-ArcSwe mice treated with NB-360 showed significantly lower in vivo PET signals than untreated animals, and were similar to the baseline 10 month old animals. The decreased [124I]RmAb158-scFv8D3 concentrations in NB-360 treated mice, quantified with PET, corresponded well with decreased A? levels measured in post mortem brain. Conclusion: A number of treatments for AD are currently studied in phase 2 and 3 clinical trials but there are limited possibilities to study their effects on the important, non-fibrillar A? forms in vivo. This study demonstrates the ability of the A? protofibril selective radioligand [124I]RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice.

Dataset Information

The ?-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-? reduction to downstream disease-relevant effects.

Publications

The β-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-β reduction to downstream disease-relevant effects.

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