共查询到20条相似文献,搜索用时 15 毫秒
1.
Neurophysiology - Alzheimer’s disease (AD) is the most common type of dementia; it is characterized by accumulations of amyloid (Aβ) plaques and neurofibrillary tangles in the brain.... 相似文献
2.
Tissue transglutaminase (TGase) has been implicated in both cell survival and apoptosis. Here we investigate the role of TGase
in β-amyloid-induced neurotoxicity using retinoic acid (RA)-differentiated, neuronal SH-SY5Y cells. We show that β-amyloid-induced
cell death was reduced in RA-differentiated SH-SY5Y cells treated with the TGase inhibitor monodansyl cadaverine. Expression
of wild-type TGase enhanced β-amyloid1-42-induced apoptosis, whereas transamidation-defective TGase did not. These effects were specific for β-amyloid-treated cells,
as TGase reversed the neurotoxic effects caused by hydrogen peroxide treatment. Enhancement of β-amyloid1-42-induced cell death by TGase was accompanied by marked increases in TGase activity in the membrane fractions and translocation
of TGase to the cell surface. Overall, these findings suggest that the ability of TGase to exhibit pro-survival versus pro-apoptotic
activity is linked to its cellular localization, with β-amyloid-induced recruitment of TGase to the cell surface accentuating
neuronal toxicity and apoptosis. 相似文献
3.
Effects of Aging and Amyloid-β Peptides on Choline Acetyltransferase Activity in Rat Brain 总被引:3,自引:0,他引:3
Choline acetyltransferase (ChAT, acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6), involved in the learning and memory processes is responsible for the synthesis of acetylcholine. There are many discrepancies in literature concerning ChAT activity during brain aging and the role of amyloid beta peptides in modulation of this enzyme. The aim of the study was to investigate the mechanism of ChAT regulation and age-related alteration of ChAT activity in different parts of the brain. Moreover the effect of A peptides on ChAT activity in adult and aged brain was investigated. The enzyme activity was determined in the brain cortex, hippocampus and striatum in adult (4-months-old), adult-aged (14-months-old) and aged (24-months-old) animals. The highest ChAT activity was observed in the striatum. We found that inhibitors of protein kinase C, A, G and phosphatase A2 have no effect on ChAT activity and that this enzyme is not dependent on calcium ions. About 70% of the total ChAT activity is present in the cytosol. Arachidonic acid significantly inhibited cytosolic form of this enzyme. In the brain cortex and striatum from aged brain ChAT activity is inhibited by 50% and 37%, respectively. The aggregated form of A 25-35 decreased significantly ChAT activity only in the aged striatum and exerted inhibitory effect on this enzyme in adult, however, statistically insignificant. ChAT activity in the striatum was diminished after exposure to 1 mM H2O2. The results from our study indicate that aging processes play a major role in inhibition of ChAT activity and that this enzyme in striatum is selectively sensitive for amyloid beta peptides. 相似文献
4.
Effects of Chronic Stress and Phenytoin on the Long-term Potentiation (LTP) in Rat Hippocampal CA1 Region 总被引:2,自引:0,他引:2
Stress is the response to stimulation from inside andoutside with complicated effects on organisms. Appropri-ate stressful reactions are helpful in resisting diseases byactivating unspecific modulation system, while severe orprolonged stresses are harmful and even induce mentaland physical disorders such as recurrent depression, post-traumatic stress disorder (PTSD), Alzheimer’s disease andepilepsy [1]. Hippocampus, a main brain region of keyimportance for learning, memory and emotion, is t… 相似文献
5.
Linping Wang Jiali Hu Yue Zhao Xiaoting Lu Qinli Zhang Qiao Niu 《Neurochemical research》2014,39(7):1338-1345
Chronic administration of aluminium has been proposed as an environmental factor that may affect some pathological changes related to neurotoxicity and Alzheimer’s disease (AD). The abnormal generation and deposition of β-amyloid (Aβ) in senile plaques are hallmark features in the brains of AD patients. Furthermore, Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. In the present study, we investigated the modulation of Aβ deposition and neurotoxicity in aluminium-maltolate-treated (0, 15, 30, 45 mmol/kg body weight via intraperitoneal injection) in experimental rats. We measured Aβ1–40 and Aβ1–42 in the cortex and hippocampus in rat brains using ELISA. Subtypes of α-secretase, β-secretase, and γ-secretase, including ADAM9, ADAM10, ADAM17 (TACE), BACE1, presenilin 1 (PS1) and nicastrin (NCT), were determined using western blotting analyses. These results indicated that aluminium-maltolate induced an AD-like behavioural deficit in rats at 30 and 45 mmol/kg body weight. Moreover, the Aβ1–42 content increased significantly, both in the cortex and hippocampus, although no changes were observed in Aβ1–40. Furthermore, ADAM9, ADAM10, and ADAM17 decreased significantly; in contrast, BACE1, PS1, and NCT showed significant increase. Taken together, these results suggest that the changes in secretases may correlate to the abnormal deposition of Aβ by aluminium in rat brains. 相似文献
6.
Non-synonymous single nucleotide polymorphisms (nsSNPs) are single base changes leading to a change to the amino acid sequence of the encoded protein. Many of these variants are associated with disease, so nsSNPs have been well studied, with studies looking at the effects of nsSNPs on individual proteins, for example, on stability and enzyme active sites. In recent years, the impact of nsSNPs upon protein–protein interactions has also been investigated, giving a greater insight into the mechanisms by which nsSNPs can lead to disease. 相似文献
7.
Mitchell R. White Ruth Kandel Shweta Tripathi David Condon Li Qi Jeffrey Taubenberger Kevan L. Hartshorn 《PloS one》2014,9(7)
Accumulation of β-Amyloid (βA) is a key pathogenetic factor in Alzheimer''s disease; however, the normal function of βA is unknown. Recent studies have shown that βA can inhibit growth of bacteria and fungi. In this paper we show that βA also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro. The 42 amino acid fragment of βA (βA42) had greater activity than the 40 amino acid fragment. Direct incubation of the virus with βA42 was needed to achieve optimal inhibition. Using quantitative PCR assays βA42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. βA42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. βA42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, βA42 increased uptake of IAV by neutrophils. βA42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that βA has antiviral activity and modulates viral interactions with phagocytes. 相似文献
8.
9.
Amyloid β peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of
Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric l-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural
l-isoforms/synthetic d-isoforms on membranes are very similar, but synthetic reverse/random l-isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated
l-isoforms of amyloid β peptides 1–40/1–42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions
of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1–40 was evaluated
by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake
system in rat hippocampal cholesterol-depleted synaptosomes to the actions of amyloid β; computational simulations were also
performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with l-peptide 1–40 but not with the reverse l-peptide 40–1, (2) 24(R)hydroxycholesterol does not interact with l-peptide 1–40 or reverse 40–1, and (3) both enantiomers can probably interact with d-peptide 1–40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not
reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid
β molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were
found. Using this procedure, globular amyloid β could retain 24(S)hydroxycholesterol and thus contribute to its pathological
accumulation in the brains of patients with Alzheimer disease. 相似文献
10.
Nicolay Ya. Orlov Tatiana G. Orlova Yana K. Reshetnyak Edward A. Burstein Narimichi Kimura 《Journal of biomolecular structure & dynamics》2013,31(4):955-968
Abstract Nucleoside diphosphate (NDP) kinases of mammals are hexamers of two sorts of randomly associated highly homologous subunits of 152 residues each and, therefore exist in cell as NDP kinase isoforms. The catalytic properties and three-dimensional structures of the isoforms are very similar. The physiological meaning of the existence of the isoforms in cells remained unclear, but studying recombinant rat NDP kinases a and β, each containing only one sort of subunits, we discovered that, in contrast to the isoenzyme β, NDP kinase α is able to interact with the complex between bleached rhodopsin and G-protein transducin in retinal rod membranes at lowered pH values (Orlov et al. FEBS Lett. 389, 186–190, 1996). In order to search for possible molecular basis of such differences between these isoenzymes, a detailed comparative study of their intrinsic fluorescence properties in a large range of solvent conditions was performed in this work. The isoenzymes α and β both contain the same three tryptophan (Trp78, 133, 1nd 149) and four tyrosine (Tyr 52, 67, 147, and 151) residues per subunit, but exhibit pronounced differences in their fluorescence properties (both in spectral positions and shape and quantum yield values) and behave differently under pH titration. Whereas NDP kinase a undergoes spectral changes in the pH range 5–7 with the mid-point at 6.2, no unequivocal indication of a structural change of NDP kinase β under pH titration from 9 to 5 was obtained. Since the pH dependencies obtained for fluorescence of isoenzyme α resembles the dependence of its binding to the rhodopsin-transducin complex it was suggested that the differences between the NDP kinase isoenzymes α and β in the pH-induced behavior, revealed by the fluorescence spectroscopy, and the differences in their ability to interact with rhodopsin-transducin complex may have the same physical nature, that would be a physico-chemical reason of possible functional dissimilarity of NDP kinase isoforms in cell. An additional analysis of three-dimensional structure of homologous NDP kinases revealed that the source of the differences in fluorescence properties and pH-titration behavior between the isoenzymes α and β may be due to the difference in their global electrostatic charges, rather than to any structural differences between them at neutral pH. The unusually high positive electrostatic potential at he deeply buried active site Tyr52 makes possible that it exists in deprotonated tyrosinate form at neutral and moderately acidic solution. Such a possibility may account for rather unusual fluorescence properties of NDP kinase α: (i) rather long-wavelength emission of NDP kinase a at ca. 340 nm at pH ca. 8 at extremely low accessibility to external quenchers and, possibly, (ii) an unusually high quantum yield value (ca. 0.42). 相似文献
11.
We examined the degradation of Alzheimer's ß-amyloid protein (1–40) by soluble and synaptic membrane fractions from post mortem human and fresh rat brain using HPLC. Most of the activity at neutral pH was in the soluble fraction. The activity was thiol and metal dependent, with a similar inhibition profile to insulin-degrading enzyme. Immunoprecipitation of insulin-degrading enzyme from the human soluble fraction using a monoclonal antibody removed over 85% of the ß-amyloid protein degrading activity. Thus insulin-degrading enzyme is the main soluble ß-amyloid degrading enzyme at neutral pH in human brain. The highest ß-amyloid protein degrading activity in the soluble fractions occurred between pH 4–5, and this activity was inhibited by pepstatin, implicating an aspartyl protease. Synaptic membranes had much lower ß-amyloid protein degrading activity than the soluble fraction. EDTA (2mM) caused over 85% inhibition of the degrading activity but inhibitors of endopeptidases –24.11, –24.15, –24.16, angiotensin converting enzyme, aminopeptidases, and carboxypeptidases had little or no effect. 相似文献
12.
Lin YH Westenbroek C Tie L Liu AH Yu HM Horst GJ Li XJ 《Neurochemical research》2006,31(12):1417-1424
Brain–pancreas relative protein (BPRP) is a novel protein that mainly expresses in brain and pancreas. In our previous study, we found that various stressors significantly decreased the expression of BPRP in pancreas in vivo, accompanied by changes in insulin and glucose levels, and that expression of BPRP in pancreas also decreased significantly in diabetic rats induced by Streptozocin (STZ). All these findings suggest that BPRP may be a glucose or insulin-sensitive protein. However, how the changes in insulin or glucose levels influence the expression of BPRP in hippocampus requires further study. Here, we investigated the effects of insulin or glucose on the expression of BPRP in primary cultured hippocampal neurons. We supplied hippocampal neurons with glucose, insulin, or supernatant from pancreatic β-cells, which secrete insulin into the supernatant. Our data showed that insulin had beneficial effect on the viability while no significant effect on the expression of BPRP in hippocampal neurons. On the contrary, 40 mM glucose or free glucose culture significantly decreased the expression of BPRP, while had no significant effect on the viability and apoptosis of hippocampal neurons. Further study showed that levels of insulin in the supernatant collected from pancreatic β-cells medium changed over days, and that supernatant increased the viability of hippocampal neurons, while it had no obvious effect on the expression of BPRP in hippocampal neurons. These results suggest that BPRP may be a glucose-sensitive protein. 相似文献
13.
Hong Yan Shen Chao Yin Qingqing Sun Menghan Ma Yingjuan Liu Xueping 《Neurochemical research》2016,41(5):1192-1199
Neurochemical Research - An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer’s disease (AD). AGEs and receptor for AGEs (RAGE) play... 相似文献
14.
《Bioscience, biotechnology, and biochemistry》2013,77(9):1842-1844
We investigated the effects of daintain/AIF-1, a novel inflammatory cytokine, on INS-1β cells. Cells incubated with daintain/AIF-1 showed decreased cell viability and glucose-stimulated insulin secretion, as well as upregulated apoptosis and NO production. These deleterious effects of daintain/AIF-1 indicate that daintain/AIF-1 plays important roles in the dysfunction of pancreatic β cells in type-1 diabetes. 相似文献
15.
Hongjie Wang Debleena Dey Ivan Carrera Dmitriy Minond Elisabetta Bianchi Shaohua Xu Madepalli K. Lakshmana 《The Journal of biological chemistry》2013,288(37):26668-26677
Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid β peptide (Aβ) in the brain is central to the pathogenesis of Alzheimer''s disease (AD). Therefore, the identification of molecules that regulate Aβ generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Aβ generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Aβ levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Aβ generation, followed by increased soluble APP-β (sAPP-β) and decreased soluble-APP-α (sAPP-α) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ generation. Finally, COPS5 levels were increased significantly in AD brains and APΔE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Aβ generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Aβ generation by stabilizing RanBP9 protein levels. 相似文献
16.
17.
We investigated the effects of daintain/AIF-1, a novel inflammatory cytokine, on INS-1β cells. Cells incubated with daintain/AIF-1 showed decreased cell viability and glucose-stimulated insulin secretion, as well as upregulated apoptosis and NO production. These deleterious effects of daintain/AIF-1 indicate that daintain/AIF-1 plays important roles in the dysfunction of pancreatic β cells in type-1 diabetes. 相似文献
18.
Saurabh Sahar Loredana Zocchi Chisato Kinoshita Emiliana Borrelli Paolo Sassone-Corsi 《PloS one》2010,5(1)
Background
Circadian rhythms govern a large array of physiological and metabolic functions. To achieve plasticity in circadian regulation, proteins constituting the molecular clock machinery undergo various post-translational modifications (PTMs), which influence their activity and intracellular localization. The core clock protein BMAL1 undergoes several PTMs. Here we report that the Akt-GSK3β signaling pathway regulates BMAL1 protein stability and activity.Principal Findings
GSK3β phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3β-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3β pathway, influences BMAL1 stability and in vivo circadian gene expression in striatal neurons.Conclusions
These findings uncover a previously unknown mechanism of circadian clock control. The GSK3β kinase phosphorylates BMAL1, an event that controls the stability of the protein and the amplitude of circadian oscillation. BMAL1 phosphorylation appears to be an important regulatory step in maintaining the robustness of the circadian clock. 相似文献19.
Emelie Janefjord Jesper L. V. Mååg Benjamin S. Harvey Scott D. Smid 《Cellular and molecular neurobiology》2014,34(1):31-42
Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a diverse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1–42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ9-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1–42. Aβ1–42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells. 相似文献
20.
Jorge-Mora T Misa-Agustiño MJ Rodríguez-González JA Jorge-Barreiro FJ Ares-Pena FJ López-Martín E 《Neurochemical research》2011,36(12):2322-2332
This study investigated the effects of microwave radiation on the PVN of the hypothalamus, extracted from rat brains. Expression
of c-Fos was used to study the pattern of cellular activation in rats exposed once or repeatedly (ten times in 2 weeks) to
2.45 GHz radiation in a GTEM cell. The power intensities used were 3 and 12 W and the Finite Difference Time Domain calculation
was used to determine the specific absorption rate (SAR). High SAR triggered an increase of the c-Fos marker 90 min or 24 h
after radiation, and low SAR resulted in c-Fos counts higher than in control rats after 24 h. Repeated irradiation at 3 W
increased cellular activation of PVN by more than 100% compared to animals subjected to acute irradiation and to repeated
non-radiated repeated session control animals. The results suggest that PVN is sensitive to 2.45 GHz microwave radiation at
non-thermal SAR levels. 相似文献