Inhibition of γ-Secretase Leads to an Increase in Presenilin-1.

Abstract:

:γ-Secretase inhibitors (GSIs) are potential therapeutic agents for Alzheimer's disease (AD); however, trials have proven disappointing. We addressed the possibility that γ-secretase inhibition can provoke a rebound effect, elevating the levels of the catalytic γ-secretase subunit, presenilin-1 (PS1). Acute treatment of SH-SY5Y cells with the GSI LY-374973 (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT) augments PS1, in parallel with increases in other γ-secretase subunits nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, yet with no increase in messenger RNA expression. Over-expression of the C-terminal fragment (CTF) of APP, C99, also triggered an increase in PS1. Similar increases in PS1 were evident in primary neurons treated repeatedly (4 days) with DAPT or with the GSI BMS-708163 (avagacestat). Likewise, rats examined after 21 days administered with avagacestat (40 mg/kg/day) had more brain PS1. Sustained γ-secretase inhibition did not exert a long-term effect on PS1 activity, evident through the decrease in CTFs of APP and ApoER2. Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development.

journal_name

Mol Neurobiol

journal_title

Molecular neurobiology

authors

Sogorb-Esteve A,García-Ayllón MS,Llansola M,Felipo V,Blennow K,Sáez-Valero J

doi

10.1007/s12035-017-0705-1

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

5047-5058

issue

6

eissn

0893-7648

issn

1559-1182

pii

10.1007/s12035-017-0705-1

journal_volume

55

pub_type

杂志文章
  • Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

    abstract::Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-015-9236-9

    authors: Sharma A,Muresanu DF,Lafuente JV,Patnaik R,Tian ZR,Buzoianu AD,Sharma HS

    更新日期:2015-10-01 00:00:00

  • Neuroprotection Induced by Transplanted CDK5 Knockdown Astrocytes in Global Cerebral Ischemic Rats.

    abstract::Cerebral ischemia is a cerebrovascular episode that generates a high incidence of death and physical and mental disabilities worldwide. Excitotoxicity, release of free radicals, and exacerbated immune response cause serious complications in motor and cognitive areas during both short and long time frames post-ischemia...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-016-0162-2

    authors: Becerra-Calixto A,Cardona-Gómez GP

    更新日期:2017-11-01 00:00:00

  • Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells.

    abstract::The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgeni...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-014-8828-0

    authors: Moutinho M,Nunes MJ,Gomes AQ,Gama MJ,Cedazo-Minguez A,Rodrigues CM,Björkhem I,Rodrigues E

    更新日期:2015-01-01 00:00:00

  • The Pathogenic Role of Ganglioside Metabolism in Alzheimer's Disease-Cholinergic Neuron-Specific Gangliosides and Neurogenesis.

    abstract::Alzheimer's disease (AD) is the most common type of dementia with clinical symptoms that include deficits in memory, judgment, thinking, and behavior. Gangliosides are present on the outer surface of plasma membranes and are especially abundant in the nervous tissues of vertebrates. Ganglioside metabolism, especially ...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章,评审

    doi:10.1007/s12035-015-9641-0

    authors: Ariga T

    更新日期:2017-01-01 00:00:00

  • The Brain NO Levels and NOS Activities Ascended in the Early and Middle Stages and Descended in the Terminal Stage in Scrapie-Infected Animal Models.

    abstract::The infections of prion agents may cause progressive and fatal neurodegenerative diseases in humans and a serial of animal species. Previous studies have proposed that the levels of nitric oxide (NO) and nitric oxide synthase (NOS) in the brains of some neurodegeneration diseases changed, while S-nitrosylation (SNO) o...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-016-9755-z

    authors: Chen LN,Sun J,Yang XD,Xiao K,Lv Y,Zhang BY,Zhou W,Chen C,Gao C,Shi Q,Dong XP

    更新日期:2017-04-01 00:00:00

  • Effects of BDNF-Transfected BMSCs on Neural Functional Recovery and Synaptophysin Expression in Rats with Cerebral Infarction.

    abstract::The purpose of this study was to investigate the effects of brain-derived neurotrophic factor (BDNF)-transfected bone marrow mesenchymal stem cells (BMSCs) on neural functional recovery and synaptophysin expression in rats with cerebral infarction (CI). A total of 120 healthy Sprague Dawley rats were randomly divided ...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-016-9946-7

    authors: Zhang Y,Qiu B,Wang J,Yao Y,Wang C,Liu J

    更新日期:2017-07-01 00:00:00

  • Paradoxical signal transduction in neurobiological systems.

    abstract::Information processing in neurobiological systems is commonly thought to rely on the assessment of a signal-to-noise ratio as the key mechanism of signal detection; it assumes and requires that both signal and noise are concurrently available. An alternative theory holds that detection proceeds by the system appreciat...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章,评审

    doi:10.1385/MN:24:1-3:145

    authors: Colpaert FC,Frégnac Y

    更新日期:2001-08-01 00:00:00

  • Transcriptional Profiling of Individual Airway Projecting Vagal Sensory Neurons.

    abstract::Bronchopulmonary sensory neurons are derived from the vagal sensory ganglia and are essential for monitoring the physical and chemical environment of the airways and lungs. Subtypes are heterogenous in their responsiveness to stimuli, phenotype, and developmental origin, but they collectively serve to regulate normal ...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-019-01782-8

    authors: Mazzone SB,Tian L,Moe AAK,Trewella MW,Ritchie ME,McGovern AE

    更新日期:2020-02-01 00:00:00

  • Combining Disrupted and Discriminative Topological Properties of Functional Connectivity Networks as Neuroimaging Biomarkers for Accurate Diagnosis of Early Tourette Syndrome Children.

    abstract::Tourette syndrome (TS) is a childhood-onset neurological disorder. To date, accurate TS diagnosis remains challenging due to its varied clinical expressions and dependency on qualitative description of symptoms. Therefore, identifying accurate and objective neuroimaging biomarkers may help improve early TS diagnosis. ...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-017-0519-1

    authors: Wen H,Liu Y,Rekik I,Wang S,Chen Z,Zhang J,Zhang Y,Peng Y,He H

    更新日期:2018-04-01 00:00:00

  • A Single Amino Acid Substitution, Found in Mammals with Low Susceptibility to Prion Diseases, Delays Propagation of Two Prion Strains in Highly Susceptible Transgenic Mouse Models.

    abstract::Specific variations in the amino acid sequence of prion protein (PrP) are key determinants of susceptibility to prion diseases. We previously showed that an amino acid substitution specific to canids confers resistance to prion diseases when expressed in mice and demonstrated its dominant-negative protective effect ag...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-019-1535-0

    authors: Otero A,Hedman C,Fernández-Borges N,Eraña H,Marín B,Monzón M,Sánchez-Martín MA,Nonno R,Badiola JJ,Bolea R,Castilla J

    更新日期:2019-09-01 00:00:00

  • Soluble Epoxide Hydrolase Inhibition Attenuates MPTP-Induced Neurotoxicity in the Nigrostriatal Dopaminergic System: Involvement of α-Synuclein Aggregation and ER Stress.

    abstract::Soluble epoxide hydrolase (sEH) is widely expressed in the mammalian brain and possesses dual enzymatic activities, including C-terminal epoxide hydrolase (C-EH) which degrades epoxyeicosatrienoic acid (EET), a beneficial arachidonic acid metabolite. In the present study, the neuroprotective effect of sEH inhibition o...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-017-0726-9

    authors: Huang HJ,Wang YT,Lin HC,Lee YH,Lin AM

    更新日期:2018-01-01 00:00:00

  • Dietary Linoleic Acid Lowering Reduces Lipopolysaccharide-Induced Increase in Brain Arachidonic Acid Metabolism.

    abstract::Linoleic acid (LA, 18:2n-6) is a precursor to arachidonic acid (AA, 20:4n-6), which can be converted by brain lipoxygenase and cyclooxygenase (COX) enzymes into various lipid mediators involved in the regulation of brain immunity. Brain AA metabolism is activated in rodents by the bacterial endotoxin, lipopolysacchari...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-016-9968-1

    authors: Taha AY,Blanchard HC,Cheon Y,Ramadan E,Chen M,Chang L,Rapoport SI

    更新日期:2017-08-01 00:00:00

  • The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9.

    abstract::The glutamate N-methyl-D-aspartate receptor (NMDAR) plays an essential role in the excitotoxic neural damage that follows ischaemic stroke. Because the sigma-1 receptor (σ1R) can regulate NMDAR transmission, exogenous and putative endogenous regulators of σ1R have been investigated using animal models of ischaemic str...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-017-0697-x

    authors: Sánchez-Blázquez P,Pozo-Rodrigálvarez A,Merlos M,Garzón J

    更新日期:2018-06-01 00:00:00

  • Subcellular Parkinson's Disease-Specific Alpha-Synuclein Species Show Altered Behavior in Neurodegeneration.

    abstract::Parkinson's disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-016-0266-8

    authors: Abdullah R,Patil KS,Rosen B,Pal R,Prabhudesai S,Lee S,Basak I,Hoedt E,Yang P,Panick K,Ho HP,Chang E,Tzoulis C,Larsen JP,Neubert TA,Alves G,Møller SG

    更新日期:2017-12-01 00:00:00

  • The Dynamics of Impaired Blood-Brain Barrier Restoration in a Rat Model of Co-morbid Injury.

    abstract::Defect in brain microperfusion is increasingly recognized as an antecedent event to Alzheimer's disease (AD) and ischemia. Nevertheless, studies on the role of impaired microperfusion as a pathological trigger to neuroinflammation, Aβ deposition as well as blood-brain barrier (BBB) disruption, and the etiological link...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-018-0904-4

    authors: Amtul Z,Yang J,Nikolova S,Lee TY,Bartha R,Cechetto DF

    更新日期:2018-10-01 00:00:00

  • N-methyl-D-aspartate receptors in the retina.

    abstract::The vertebrate retina is a "genuine neural center" (Ramón y Cajal), in which glutamate is a major excitatory neurotransmitter. Both N-methyl-D-aspartate (NMDA) and non-NMDA receptors are expressed in the retina. Although non-NMDA receptors and/or metabotropic glutamate receptors are generally thought to be responsible...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章,评审

    doi:10.1385/MN:34:3:163

    authors: Shen Y,Liu XL,Yang XL

    更新日期:2006-12-01 00:00:00

  • Deletion of Semaphorin 3F in Interneurons Is Associated with Decreased GABAergic Neurons, Autism-like Behavior, and Increased Oxidative Stress Cascades.

    abstract::Autism and epilepsy are diseases which have complex genetic inheritance. Genome-wide association and other genetic studies have implicated at least 500+ genes associated with the occurrence of autism spectrum disorders (ASD) including the human semaphorin 3F (Sema 3F) and neuropilin 2 (NRP2) genes. However, the geneti...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-018-1450-9

    authors: Li Z,Jagadapillai R,Gozal E,Barnes G

    更新日期:2019-08-01 00:00:00

  • GTP-binding proteins and potassium channels involved in synaptic plasticity and learning.

    abstract::Inhibition of potassium channels is possibly the first step in the sequence of biochemical events leading to memory formation. These channels appear to be regulated directly or indirectly by GTP-binding proteins (G proteins), which may themselves be affected by phosphorylation and dephosphorylation in response to elev...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章,评审

    doi:10.1007/BF02935554

    authors: Nelson TJ,Alkon DL

    更新日期:1991-01-01 00:00:00

  • Molecular Basis of Sex Difference in Neuroprotection induced by Hypoxia Preconditioning in Zebrafish.

    abstract::Hypoxia, the major cause of ischemic injury, leads to debilitating disease in infants via birth asphyxia and cerebral palsy, whereas in adults via heart attack and stroke. A widespread, natural protective phenomenon termed 'hypoxic preconditioning' (PH) occurs when prior exposures to hypoxia eventually result in robus...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-020-02091-1

    authors: Das T,Soren K,Yerasi M,Kamle A,Kumar A,Chakravarty S

    更新日期:2020-12-01 00:00:00

  • Vitamin B6 Reduces Neurochemical and Long-Term Cognitive Alterations After Polymicrobial Sepsis: Involvement of the Kynurenine Pathway Modulation.

    abstract::Neurological dysfunction as a result of neuroinflammation has been reported in sepsis and cause high mortality. High levels of cytokines stimulate the formation of neurotoxic metabolites by kynurenine (KYN) pathway. Vitamin B6 (vit B6) has anti-inflammatory and antioxidant properties and also acts as a cofactor for en...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-017-0706-0

    authors: Danielski LG,Giustina AD,Goldim MP,Florentino D,Mathias K,Garbossa L,de Bona Schraiber R,Laurentino AOM,Goulart M,Michels M,de Queiroz KB,Kohlhof M,Rezin GT,Fortunato JJ,Quevedo J,Barichello T,Dal-Pizzol F,Coimbra RS,

    更新日期:2018-06-01 00:00:00

  • Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory.

    abstract::Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contex...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-015-9093-6

    authors: Jiang L,Mao R,Zhou Q,Yang Y,Cao J,Ding Y,Yang Y,Zhang X,Li L,Xu L

    更新日期:2016-03-01 00:00:00

  • Rostral-Caudal Hippocampal Functional Convergence Is Reduced Across the Alzheimer's Disease Spectrum.

    abstract::Beginning in the early stages of Alzheimer's disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a met...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-019-01671-0

    authors: Therriault J,Wang S,Mathotaarachchi S,Pascoal TA,Parent M,Beaudry T,Shin M,Al B,Kang MS,Ng KP,Dansereau C,Park MTM,Fonov V,Carbonell F,Zimmer E,Chakravarty MM,Bellec P,Gauthier S,Rosa-Neto P,Alzheimer’s Disease Neur

    更新日期:2019-12-01 00:00:00

  • α-Synuclein elevation in human neurodegenerative diseases: experimental, pathogenetic, and therapeutic implications.

    abstract::The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progre...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章,评审

    doi:10.1007/s12035-012-8329-y

    authors: Ulusoy A,Di Monte DA

    更新日期:2013-04-01 00:00:00

  • Roles of micro-opioid receptors in GABAergic synaptic transmission in the striosome and matrix compartments of the striatum.

    abstract::The striatum is divided into two compartments, the striosomes and extrastriosomal matrix, which differ in several cytochemical markers, input-output connections, and time of neurogenesis. Since it is thought that limbic, reward-related information and executive aspects of behavioral information may be differentially p...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章,评审

    doi:10.1007/s12035-008-8023-2

    authors: Miura M,Masuda M,Aosaki T

    更新日期:2008-04-01 00:00:00

  • Maternal Separation-Induced Histone Acetylation Correlates with BDNF-Programmed Synaptic Changes in an Animal Model of PTSD with Sex Differences.

    abstract::Maternal separation (MS) causes long-lasting epigenetic changes in the brain and increases vulnerability to traumatic events in adulthood. Of interest, there may be sex-specific differences in these epigenetic changes. In this study, the extent of histone acetylation in the hippocampus (HIP) and the expression of BDNF...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-020-02224-6

    authors: Sun H,Zhang X,Kong Y,Gou L,Lian B,Wang Y,Jiang L,Li Q,Sun H,Sun L

    更新日期:2020-11-27 00:00:00

  • Leukemia Inhibitory Factor Protects Neurons from Ischemic Damage via Upregulation of Superoxide Dismutase 3.

    abstract::Leukemia inhibitory factor (LIF) has been shown to protect oligodendrocytes from ischemia by upregulating endogenous antioxidants. The goal of this study was to determine whether LIF protects neurons during stroke by upregulating superoxide dismutase 3 (SOD3). Animals were administered phosphate-buffered saline (PBS) ...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-015-9587-2

    authors: Davis SM,Collier LA,Leonardo CC,Seifert HA,Ajmo CT Jr,Pennypacker KR

    更新日期:2017-01-01 00:00:00

  • Dopamine Promotes Ascorbate Release from Retinal Neurons: Role of D1 Receptors and the Exchange Protein Directly Activated by cAMP type 2 (EPAC2).

    abstract::Ascorbate, the reduced form of vitamin C, is highly concentrated in the central nervous system (CNS), including the retina, where it plays important physiological functions. In the CNS, the plasma membrane transporter sodium vitamin C co-transporter 2 (SVCT2) is responsible for ascorbate transport in neurons. The neur...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-018-0962-7

    authors: da Encarnação TG,Portugal CC,Nogueira CE,Santiago FN,Socodato R,Paes-de-Carvalho R

    更新日期:2018-10-01 00:00:00

  • Effects of Fatty Acid Amide Hydrolase Inhibitors Acute Administration on the Positive and Cognitive Symptoms of Schizophrenia in Mice.

    abstract::The connection between the endocannabinoid system (ECS) and schizophrenia is supported by a large body of research. The ECS is composed of two types cannabinoid (CB: CB1 and CB2) receptors and their endogenous ligands, endocannabinoids. The best-known endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-019-1596-0

    authors: Kruk-Slomka M,Banaszkiewicz I,Slomka T,Biala G

    更新日期:2019-11-01 00:00:00

  • Social Isolation During Adolescence Strengthens Retention of Fear Memories and Facilitates Induction of Late-Phase Long-Term Potentiation.

    abstract::Social isolation during the vulnerable period of adolescence produces emotional dysregulation that often manifests as abnormal behavior in adulthood. The enduring consequence of isolation might be caused by a weakened ability to forget unpleasant memories. However, it remains unclear whether isolation affects unpleasa...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-014-8917-0

    authors: Liu JH,You QL,Wei MD,Wang Q,Luo ZY,Lin S,Huang L,Li SJ,Li XW,Gao TM

    更新日期:2015-12-01 00:00:00

  • (S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5.

    abstract::The neuronal circuit remodels during development as well as in human neuropathologies such as epilepsy. Neurite outgrowth is an obligatory step in these events. We recently reported that alterations in the phosphorylation state of an axon specification/guidance protein, the collapsin response mediator protein 2 (CRMP2...

    journal_title:Molecular neurobiology

    pub_type: 杂志文章

    doi:10.1007/s12035-015-9141-2

    authors: Moutal A,François-Moutal L,Perez-Miller S,Cottier K,Chew LA,Yeon SK,Dai J,Park KD,Khanna M,Khanna R

    更新日期:2016-04-01 00:00:00