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Larissa B Patterson, David M Parichy
Migratory cells derived from the neural crest encounter both local cues and more distant signals as they effect specific morphogenetic outcomes. In this issue of Developmental Cell, Zhang et al. (2018) reveal how zebrafish melanophores use the sheddase Bace2 to "tune out" insulin signaling, thereby allowing stripes to form.
June 4, 2018: Developmental Cell
Yan M Zhang, Milena A Zimmer, Talia Guardia, Scott J Callahan, Chandrani Mondal, Julie Di Martino, Toshimitsu Takagi, Myles Fennell, Ralph Garippa, Nathaniel R Campbell, Jose Javier Bravo-Cordero, Richard M White
Patterning of vertebrate melanophores is essential for mate selection and protection from UV-induced damage. Patterning can be influenced by circulating long-range factors, such as hormones, but it is unclear how their activity is controlled in recipient cells to prevent excesses in cell number and migration. The zebrafish wanderlust mutant harbors a mutation in the sheddase bace2 and exhibits hyperdendritic and hyperproliferative melanophores that localize to aberrant sites. We performed a chemical screen to identify suppressors of the wanderlust phenotype and found that inhibition of insulin/PI3Kγ/mTOR signaling rescues the defect...
May 21, 2018: Developmental Cell
Fuchen Liu, Yun Zhang, Zonglai Liang, Qianwen Sun, Heng Liu, Juan Zhao, Jingwen Xu, Jinfan Zheng, Yan Yun, Xiao Yu, Weihong Song, Xiulian Sun
Potassium channel Kv2.1 regulates potassium current in cortical neurons and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. BACE2 is an aspartyl protease to cleave APP to prevent the generation of Aβ, a central component of neuritic plaques in Alzheimer's brain. We now identified Kv2.1 as a novel substrate of BACE2. We found that BACE2 cleaved Kv2.1 at Thr376, Ala717, and Ser769 sites and disrupted Kv2...
April 27, 2018: Molecular Psychiatry
Patrik Johansson, Karin Kaspersson, Ian K Gurrell, Elisabeth Bäck, Susanna Eketjäll, Clay W Scott, Gvido Cebers, Philip Thorne, Michael J McKenzie, Haydn Beaton, Paul Davey, Karin Kolmodin, Jörg Holenz, Mark E Duggan, Samantha Budd Haeberlein, Roland W Bürli
BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles...
April 26, 2018: Journal of Medicinal Chemistry
Brian T O'Neill, Elizabeth M Beck, Christopher R Butler, Charles E Nolan, Cathleen Gonzales, Lei Zhang, Shawn D Doran, Kimberly Lapham, Leanne M Buzon, Jason K Dutra, Gabriela Barreiro, Xinjun Hou, Luis A Martinez-Alsina, Bruce N Rogers, Anabella Villalobos, John C Murray, Kevin Ogilvie, Erik A LaChapelle, Cheng Chang, Lorraine F Lanyon, Claire M Steppan, Ashley Robshaw, Katherine Hales, Germaine G Boucher, Karamjeet Pandher, Christopher Houle, Claude W Ambroise, David Karanian, David Riddell, Kelly R Bales, Michael A Brodney
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype...
May 24, 2018: Journal of Medicinal Chemistry
Liang Zhao, Yan Xiao, Jin Xiu, Long-Chun Tan, Zhi-Zhong Guan
The treatment of neurodegenerative diseases with statins has drawn increasing attention, but the related molecular mechanisms remain elusive. To examine the pleiotropic cholesterol-independent effects of statins in connection with the treatment of Alzheimer disease, we probed the influence of lovastatin on the metabolism of amyloid precursor protein (APP) , expression of nicotinic acetylcholine receptors (nAChRs), and activity of mitogen-activated protein kinase in primary cultured neurons and SH-SY5Y cells over-expressing human APP670/671...
January 13, 2018: American Journal of Pathology
Joshua A Kulas, Kendra L Puig, Colin K Combs
The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer's disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes...
October 2017: Journal of Endocrinology
Maria Chiara Pelleri, Elena Gennari, Chiara Locatelli, Allison Piovesan, Maria Caracausi, Francesca Antonaros, Alessandro Rocca, Costanza Maria Donati, Letizia Conti, Pierluigi Strippoli, Marco Seri, Lorenza Vitale, Guido Cocchi
Among Down syndrome (DS) children, 40-50% have congenital heart disease (CHD). Although trisomy 21 is not sufficient to cause CHD, three copies of at least part of chromosome 21 (Hsa21) increases the risk for CHD. In order to establish a genotype-phenotype correlation for CHD in DS, we built an integrated Hsa21 map of all described partial trisomy 21 (PT21) cases with sufficient indications regarding presence or absence of CHD (n=107), focusing on DS PT21 cases. We suggest a DS CHD candidate region on 21q22...
October 2017: Genomics
Riqiang Yan
BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer's disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years...
2017: Frontiers in Molecular Neuroscience
Gema Alcarraz-Vizán, Carlos Castaño, Montse Visa, Joel Montane, Joan-Marc Servitja, Anna Novials
BACE2 (β-site APP-cleaving enzyme 2) is a protease expressed in the brain, but also in the pancreas, where it seems to play a physiological role. Amyloidogenic diseases, including Alzheimer's disease and type 2 diabetes (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. In T2D, islet amyloid polypeptide (IAPP) deposits have been shown to be a pathogenic key feature of the disease. The aim of the present study was to investigate the effect of BACE2 modulation on β-cell alterations in a mouse model of T2D induced by IAPP overexpression...
August 2017: Cellular and Molecular Life Sciences: CMLS
Erdem B Dashinimaev, Alexander S Artyuhov, Alexey P Bolshakov, Ekaterina A Vorotelyak, Andrey V Vasiliev
People with Down syndrome (DS) are at high risk of developing pathology similar to Alzheimer's disease (AD). Modeling of this pathology in vitro may be useful for studying this phenomenon. In this study, we analyzed three different cultures of neural cells carrying trisomy of chromosome 21, which were generated by directed differentiation from induced pluripotent stem cells (iPS cells). We report here that in vitro generated DS neural cells have abnormal metabolism of amyloid-β (Aβ) manifested by increased secretion and accumulation of Aβ granules of Aβ42 pathological isoform with upregulated expression of the APP gene...
2017: Journal of Alzheimer's Disease: JAD
Jack D Scott, Sarah W Li, Andrew P J Brunskill, Xia Chen, Kathleen Cox, Jared N Cumming, Mark Forman, Eric J Gilbert, Robert A Hodgson, Lynn A Hyde, Qin Jiang, Ulrich Iserloh, Irina Kazakevich, Reshma Kuvelkar, Hong Mei, John Meredith, Jeffrey Misiaszek, Peter Orth, Lana M Rossiter, Meagan Slater, Julie Stone, Corey O Strickland, Johannes H Voigt, Ganfeng Wang, Hongwu Wang, Yusheng Wu, William J Greenlee, Eric M Parker, Matthew E Kennedy, Andrew W Stamford
Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans...
December 8, 2016: Journal of Medicinal Chemistry
Zhixiong Ma, Weiliang Jiang, Eric Erquan Zhang
Alzheimer's disease (AD) is a circadian clock-related disease. However, it is not very clear whether pre-symptomatic AD leads to circadian disruption or whether malfunction of circadian rhythms exerts influence on development of AD. Here, we report a functional clock that exists in the hippocampus. This oscillator both receives input signals and maintains the cycling of the hippocampal Per2 gene. One of the potential inputs to the oscillator is orexin signaling, which can shorten the hippocampal clock period and thereby regulate the expression of clock-controlled-genes (CCGs)...
October 31, 2016: Scientific Reports
Maricarmen Hernández-Rodríguez, José Correa-Basurto, Antonia Gutiérrez, Javier Vitorica, Martha C Rosales-Hernández
Inhibition of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases...
November 29, 2016: European Journal of Medicinal Chemistry
Anne Marie Madore, Vanessa T Vaillancourt, Emmanuelle Bouzigon, Chloé Sarnowski, Florent Monier, Marie Hélène Dizier, Florence Demenais, Catherine Laprise
PURPOSE: Interleukin-1 (IL-1) plays a key role in inflammation and immunity and its decoy receptor, IL-1R2, has been implicated in transcriptomic and genetic studies of asthma. METHODS: Two large asthma family collections, the French-Canadian Saguenay-Lac-St-Jean (SLSJ) study and the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA), were used to investigate the association of SNPs in 10 genes that modulate IL-1R2 activities with asthma, allergic asthma, and atopy...
September 2016: Allergy, Asthma & Immunology Research
Derya R Shimshek, Laura H Jacobson, Carine Kolly, Natasa Zamurovic, Kamal Kumar Balavenkatraman, Laurent Morawiec, Robert Kreutzer, Juliane Schelle, Mathias Jucker, Barbara Bertschi, Diethilde Theil, Annabelle Heier, Karine Bigot, Karen Beltz, Rainer Machauer, Irena Brzak, Ludovic Perrot, Ulf Neumann
Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD)...
February 25, 2016: Scientific Reports
Douglas E Linn, Kathryn L Penney, Roderick T Bronson, Lorelei A Mucci, Zhe Li
TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency...
April 1, 2016: Cancer Research
Nur Hanisah Azmi, Maznah Ismail, Norsharina Ismail, Mustapha Umar Imam, Noorjahan Banu Mohammed Alitheen, Maizaton Atmadini Abdullah
The pathogenesis of Alzheimer's disease involves complex etiological factors, of which the deposition of beta-amyloid (Aβ) protein and oxidative stress have been strongly implicated. We explored the effects of H2O2, which is a precursor for highly reactive hydroxyl radicals, on neurotoxicity and genes related to AD on neuronal cells. Candidate bioactive compounds responsible for the effects were quantified using HPLC-DAD. Additionally, the effects of germinated brown rice (GBR) on the morphology of Aβ(1-42) were assessed by Transmission Electron Microscopy and its regulatory effects on gene expressions were explored...
2015: Evidence-based Complementary and Alternative Medicine: ECAM
Ingrid C Rulifson, Ping Cao, Li Miao, David Kopecky, Linda Huang, Ryan D White, Kim Samayoa, Jonitha Gardner, Xiaosu Wu, Kui Chen, Trace Tsuruda, Oliver Homann, Helene Baribault, Harvey Yamane, Tim Carlson, Jed Wiltzius, Yang Li
Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets...
2016: PloS One
Soraia Barão, Diederik Moechars, Stefan F Lichtenthaler, Bart De Strooper
The protease β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is required for the production of the amyloid-β (Aβ) peptide, which is central to the pathogenesis of Alzheimer's disease (AD). Chronic inhibition of this protease may temper amyloid production and cure or prevent AD. However, while BACE1 inhibitors are being pushed forward as drug candidates, a remarkable gap in knowledge on the physiological functions of BACE1 and its close homolog BACE2 becomes apparent. Here we discuss the major discoveries of the past 3 years concerning BACE1 biology and to what extent these could limit the use of BACE1 inhibitors in the clinic...
March 2016: Trends in Neurosciences
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