Abstract：
:Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Dovey HF,John V,Anderson JP,Chen LZ,de Saint Andrieu P,Fang LY,Freedman SB,Folmer B,Goldbach E,Holsztynska EJ,Hu KL,Johnson-Wood KL,Kennedy SL,Kholodenko D,Knops JE,Latimer LH,Lee M,Liao Z,Lieberburg IM,Motter RN,doi
10.1046/j.1471-4159.2001.00012.xkeywords:
subject
Has Abstractpub_date
2001-01-01 00:00:00pages
173-81issue
1eissn
0022-3042issn
1471-4159journal_volume
76pub_type
杂志文章abstract：:Leucine and beta-(+/-)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) stimulated, in a dose-dependent manner, reductive amination of 2-oxoglutarate in rat brain synaptosomes treated with Triton X-100. The concentration dependence curves were sigmoid, with 10-15-fold stimulations at 15 mM leucine (or BCH); oxidat...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1990.tb01967.x
更新日期：1990-04-01 00:00:00
abstract：:Progress has been made in Guillain-Barré syndrome, a post-infectious autoimmune neuropathy, especially on identifying Campylobacter jejuni genes responsible for the development and determinant of clinical features. C. jejuni strains carrying a sialyltransferase gene (cst-II), which is essential for the biosynthesis of...
journal_title：Journal of neurochemistry
pub_type： 杂志文章,评审
doi：10.1111/j.1471-4159.2007.04707.x
更新日期：2007-11-01 00:00:00
abstract：:Rabbit retinas were maintained in a physiological state in vitro and exposed to 0.5-h pulses of labeled leucine. Protein synthesis was determined from incorporation of the label, and degradation from its subsequent release. The retinas were treated as test-control pairs. The control retina remained in darkness while t...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1980.tb12499.x
更新日期：1980-07-01 00:00:00
abstract：:In a study employing mouse brain synaptosomes and synaptosomal sonicates, the complete metabolic machinery was found to be present for transport of arginine into synaptosomes, its conversion to ornithine, and the formation from the latter of glutamic acid, gamma-aminobutyric acid, and proline. The results show that a ...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1984.tb12719.x
更新日期：1984-04-01 00:00:00
abstract：:3,4-Dihydroxyphenylethylamine (dopamine) D2 receptor agonists, including BHT 920 and bromocriptine, and the potassium channel opener minoxidil share the property of hyperpolarizing the plasma membrane by activating voltage-dependent potassium channels. These drugs were tested for their ability to inhibit the cyclic AM...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1992.tb11016.x
更新日期：1992-11-01 00:00:00
abstract：:Effects of protein kinase C on protein stability and activity of rat AANAT were investigated in vitro and in vivo. When COS-7 cells transfected with AANAT cDNA were treated with phorbol 12-myristate 13-acetate (PMA), both the activity and protein level of AANAT were increased. These effects of PMA were blocked by GF10...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2004.02495.x
更新日期：2004-07-01 00:00:00
abstract：:Significant progress has been made in the identification of intrinsic and extrinsic factors involved in the development of nervous system. It is remarkable that the establishment and maintenance of the asymmetrical architecture of a neuron is coordinated by a limited repertoire of signalling machineries. However, the ...
journal_title：Journal of neurochemistry
pub_type： 杂志文章,评审
doi：10.1111/j.1471-4159.2006.04372.x
更新日期：2007-05-01 00:00:00
abstract：:Synaptosomes and mitochondria were isolated from the brains of warm-adapted, hibernating, and cold-acclimated golden hamsters (Mesocricetus auratus). Lipid extracts of these subcellular fractions were prepared and assayed for plasmenylethanolamine (ethanolamine plasmalogen) and cholesterol levels. The ganglioside comp...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1983.tb08098.x
更新日期：1983-04-01 00:00:00
abstract：:Astrocytes have important roles in control of extracellular environment, de novo synthesis of neurotransmitters, and regulation of neurotransmission and blood flow. All of these functions require energy, suggesting that astrocytic metabolism should rise and fall with changes in neuronal activity and that brain imaging...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2007.04859.x
更新日期：2007-11-01 00:00:00
abstract：:Clearance rates for serotonin (5-HT) in heterozygote (+/-) and homozygote (-/-) serotonin transporter (5-HTT) knockout (KO) mice have not been determined in vivo. Moreover, the effect of selective serotonin reuptake inhibitors (SSRIs) on 5-HT clearance in these mice has not been examined. In this study, the rate of cl...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2003.01836.x
更新日期：2003-07-01 00:00:00
abstract：:Microglia, the resident macrophage of the brain, can release substances that aid neuronal development, differentiation and survival. We have investigated the effects of non-activated microglia on the survival of cultured rat cerebellar granule neurones. Microglial-conditioned medium, collected from primary rat microgl...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2004.02461.x
更新日期：2004-07-01 00:00:00
abstract：:This article reports the results of a systematic investigation of the different types of antibodies produced in the course of a long-term immunization of rats with mouse nerve growth factor (NGF). We have characterized three types of monoclonal antibodies, namely: (1) antibodies that bind to NGF and inhibit its bindin...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1988.tb10565.x
更新日期：1988-04-01 00:00:00
abstract：:Brain-derived neurotrophic factor (BDNF) promotes the survival of various neuronal populations and thus shows potential in the treatment of neurodegenerative disease. However, BDNF is not pharmacokinetically optimal for use as a therapeutic agent. As a step toward the development of low-molecular-weight BDNF-like drug...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1998.70041712.x
更新日期：1998-04-01 00:00:00
abstract：:Primary dopaminergic neuronal cultures with increased superoxide dismutase (SOD) activity were established for studying the role of superoxide anion (O2-) in 1-methyl-4-phenylpyridinium (MPP+)-induced degeneration of dopamine (DA) neurons. Mean SOD activity in cultures prepared from transgenic (human) Cu/Zn SOD (hSOD1...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1997.68010058.x
更新日期：1997-01-01 00:00:00
abstract：:Alzheimer's amyloid beta-protein (Abeta) has been reported to potentiate glutamate toxicity in neurons, but very little is known about interaction between Abeta and glutamate in astrocytes. Therefore, in the present study, we investigated the effects of Abeta and glutamate on morphology of astrocytes. Cultured rat cor...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2000.0740280.x
更新日期：2000-01-01 00:00:00
abstract：:To investigate regulation of D2 receptor (D2R) gene expression by protein kinases, we evaluated effects of constitutively active MAPK kinase kinase (MEKK), Ca2+/calmodulin-dependent protein kinase (CaMK) II, CaMKIV and cyclic AMP-dependent protein kinase (PKA) on D2R promoter activity using luciferase reporter gene as...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2002.01180.x
更新日期：2002-11-01 00:00:00
abstract：:The effects of treatment with the anti-convulsant agents, lamotrigine and riluzole were compared with gabapentin in a rat experimental model of neuropathic pain. Rats were treated intraperitoneally, with gabapentin (30, 100 and 300 mg/kg), lamotrigine (2, 10 and 50 mg/kg) or riluzole (6 and 12 mg/kg) prior to, and eve...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.04304.x
更新日期：2007-03-01 00:00:00
abstract：:Highly purified human serum cholinesterase (EC 3.1.1.8, also known as pseudocholinesterase and butyrylcholinesterase) had peptidase activity toward substance P. Digestion of substance P was monitored by high performance liquid chromatography, which separated three product peptides. The cleavages occurred sequentially....
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1982.tb04707.x
更新日期：1982-07-01 00:00:00
abstract：:The subcellular localization of organelles, mRNAs and proteins is particularly challenging in neurons. Owing to their extended morphology, with axons in humans exceeding a meter in length, in addition to which they are not renewed but persist for the entire lifespan, it is no surprise that neurons are highly vulnerabl...
journal_title：Journal of neurochemistry
pub_type： 杂志文章,评审
doi：10.1111/j.1471-4159.2006.03955.x
更新日期：2006-08-01 00:00:00
abstract：:The rat ATP P2X4 receptor was expressed in Xenopus laevis oocytes to assess the effect of zinc and copper as possible regulators of purinergic mechanisms. ATP applied for 20 s evoked an inward cationic current with a median effective concentration (EC50) of 21.4+/-2.8 microM and a Hill coefficient (nH) of 1.5+/-0.1. C...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2000.0741529.x
更新日期：2000-04-01 00:00:00
abstract：:Early malnutrition is a risk factor for depression and schizophrenia. Since the offspring of malnourished dams exhibit increased brain levels of serotonin (5-HT), a tryptophan-derived neurotransmitter involved in the pathophysiology of these mental disorders, it is believed that the deleterious effects of early malnut...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.13874
更新日期：2017-01-01 00:00:00
abstract：:The activities of choline acetyltransferase (CAT) and glutamic acid decarboxylase (GAD), markers of cholinergic and GABAergic terminals, were measured in growing and adult Gunn rats, which possess an autosomal recessive gene for jaundice or kernicterus. In the olfactory tubercle, hippocampus, neostriatum, thalamus, an...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1981.tb04499.x
更新日期：1981-10-01 00:00:00
abstract：:Acetyl-L-carnitine (ALCAR) is an endogenous metabolic intermediate that facilitates the influx and efflux of acetyl groups across the mitochondrial inner membrane. Exogenously administered ALCAR has been used as a nutritional supplement and also as an experimental drug with reported neuroprotective properties and effe...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2010.06807.x
更新日期：2010-08-01 00:00:00
abstract：:Brain-derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF-mediated pro-death signalling in hyp...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.14609
更新日期：2019-01-01 00:00:00
abstract：:PC12D cells, a new subline of conventional PC12 cells, respond not only to nerve growth factor but also to cyclic AMP by extending their neurites. These cells are flat in shape and are similar in appearance to PC12 cells that have been treated with nerve growth factor for a few days. In both cell lines, we have charac...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1989.tb02538.x
更新日期：1989-03-01 00:00:00
abstract：:The role of neuroactive steroids and GABA(A) receptors in the generation of spontaneous spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The plasma, cerebrocortical, and thalamic concentrations of the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5a...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2008.05538.x
更新日期：2008-09-01 00:00:00
abstract：:The effect of a unilateral perinatal hypoxic-ischemic brain injury on dopamine D1 and D2 receptors and uptake sites was investigated in rats by using in vitro quantitative binding autoradiography, 2-3 weeks after the insult. We observed significant decreases in the Bmax and KD for [3H]SCH 23390-labeled D1 and in the B...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1991.tb06409.x
更新日期：1991-12-01 00:00:00
abstract：:Neuronal differentiation requires exquisitely timed cell cycle arrest for progenitors to acquire an appropriate neuronal cell fate and is achieved by communication between soluble signals, such as growth factors and extracellular matrix molecules. Here we report that the expression of TIMP-2, a matrix metalloproteinas...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.03855.x
更新日期：2006-07-01 00:00:00
abstract：:Increasing evidence suggests that the dopaminergic degeneration which characterizes Parkinson's disease starts in the striatal dopamine terminals and progresses retrogradely to the body of dopamine cells in the substantia nigra. The role of striatal astrocytes in the striatal initiation of the dopaminergic degeneratio...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.13684
更新日期：2016-10-01 00:00:00
abstract：:Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its ro...
journal_title：Journal of neurochemistry
pub_type： 杂志文章,多中心研究
doi：10.1111/jnc.13719
更新日期：2016-10-01 00:00:00
