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1.
Emerging evidence suggests that dysregulation stress hormones, such as glucocorticoids, in aged persons put them at a higher risk to develop Alzheimer's disease (AD). However, the mechanisms underlying such vulnerability remain to be unraveled. Pharmacologic inhibition of 5‐lipoxygenase (5LO), an active player in AD pathogenesis whose protein level increases with aging in the human, has been shown to blunt glucocorticoid‐mediated amyloid β (Ab) formation in vitro. In this article, we investigated the role of this pathway in modulating the development of the corticosteroid‐dependent AD‐like phenotype in the triple transgenic mice (3xTg). Dexamethasone was administered for 1 week to 3xTg or 3xTg genetically deficient for 5LO (3xTg/5LO?/?) mice, and its effect on memory, amyloid‐β and tau levels, and metabolism assessed. At the end of the treatment, we observed that dexamethasone did not induce changes in behavior. Compared with controls, treated mice did not show significant alterations in brain soluble Aβ levels. While total tau protein levels were unmodified in all groups, we found that dexamethasone significantly increased tau phosphorylation at S396, as recognized by the antibody PHF‐13, which was specifically associated with an increase in the GSK3β activity. Additionally, dexamethasone‐treated mice had a significant increase in the tau insoluble fraction and reduction in the postsynaptic protein PDS‐95. By contrast, these modifications were blunted in the 3xTg/5LO?/? mice. Our findings highlight the functional role that 5LO plays in stress‐induced AD tau pathology and support the hypothesis that pharmacologic inhibition of this enzyme could be a useful tool for individuals with this risk factor. 相似文献
2.
Swarup K. Chakrabarti Banumathi K. Cole Yeshao Wen Susanna R. Keller Jerry L. Nadler 《Obesity (Silver Spring, Md.)》2009,17(9):1657-1663
Inflammation and insulin resistance associated with visceral obesity are important risk factors for the development of type 2 diabetes, atherosclerosis, and the metabolic syndrome. The 12/15‐lipoxygenase (12/15‐LO) enzyme has been linked to inflammatory changes in blood vessels that precede the development of atherosclerosis. The expression and role of 12/15‐LO in adipocytes have not been evaluated. We found that 12/15‐LO mRNA was dramatically upregulated in white epididymal adipocytes of high‐fat fed mice. 12/15‐LO was poorly expressed in 3T3‐L1 fibroblasts and was upregulated during differentiation into adipocytes. Interestingly, the saturated fatty acid palmitate, a major component of high fat diets, augmented expression of 12/15‐LO in vitro. When 3T3‐L1 adipocytes were treated with the 12/15‐LO products, 12‐hydroxyeicosatetranoic acid (12(S)‐HETE) and 12‐hydroperoxyeicosatetraenoic acid (12(S)‐HPETE), expression of proinflammatory cytokine genes, including tumor necrosis factor‐α (TNF‐α), monocyte chemoattractant protein 1 (MCP‐1), interleukin 6 (IL‐6), and IL‐12p40, was upregulated whereas anti‐inflammatory adiponectin gene expression was downregulated. 12/15‐LO products also augmented c‐Jun N‐terminal kinase 1 (JNK‐1) phosphorylation, a known negative regulator of insulin signaling. Consistent with impaired insulin signaling, we found that insulin‐stimulated 3T3‐L1 adipocytes exhibited decreased IRS‐1(Tyr) phosphorylation, increased IRS‐1(Ser) phosphorylation, and impaired Akt phosphorylation when treated with 12/15‐LO product. Taken together, our data suggest that 12/15‐LO products create a proinflammatory state and impair insulin signaling in 3T3‐L1 adipocytes. Because 12/15‐LO expression is upregulated in visceral adipocytes by high‐fat feeding in vivo and also by addition of palmitic acid in vitro, we propose that 12/15‐LO plays a role in promoting inflammation and insulin resistance associated with obesity. 相似文献
3.
Brain 5‐lipoxygenase over‐expression worsens memory,synaptic integrity,and tau pathology in the P301S mice 下载免费PDF全文
Progressive accumulation of highly phosphorylated tau protein isoforms is the main feature of a group of neurodegenerative diseases collectively called tauopathies. Data from human and animal models of these diseases have shown that neuroinflammation often accompanies their pathogenesis. The 5‐lipoxygenase (5LO) is an enzyme widely expressed in the brain and a source of potent pro‐inflammatory mediators, while its pharmacological inhibition modulates the phenotype of a tau transgenic mouse model, the htau mice. By employing an adeno‐associated viral vector system to over‐express 5LO in the brain, we examined its contribution to the behavioral deficits and neuropathology in a different transgenic mouse model of tauopathy, the P301S mouse line. Compared with controls, 5LO‐targeted gene brain over‐expression in these mice resulted in a worsening of behavioral and motor deficits. Over‐expression of 5LO resulted in microglia and astrocyte activation and significant synaptic pathology, which was associated with a significant elevation of tau phosphorylation at specific epitopes, tau insoluble fraction, and activation of the cdk5 kinase. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes via the cdk5 kinase pathway. These data demonstrate that 5LO plays a direct role in tau phosphorylation and is an active player in the development of the entire tau phenotype. They provide further support to the hypothesis that 5LO is a viable therapeutic target for the treatment and/or prevention of human tauopathy. 相似文献
4.
Jian‐Guo Li Carlos Barrero Sapna Gupta Warren D. Kruger Salim Merali Domenico Praticò 《Aging cell》2017,16(2):273-280
Elevated levels of homocysteinemia (Hcy), a risk factor for late‐onset Alzheimer's disease (AD), have been associated with changes in cell methylation. Alzheimer's disease is characterized by an upregulation of the 5‐lipoxygenase (5LO), whose promoter is regulated by methylation. However, whether Hcy activates 5LO enzymatic pathway by influencing the methylation status of its promoter remains unknown. Brains from mice with high Hcy were assessed for the 5LO pathway and neuronal cells exposed to Hcy implemented to study the mechanism(s) regulating 5LO expression levels and the effect on amyloid β formation. Diet‐ and genetically induced high Hcy resulted in 5LO protein and mRNA upregulation, which was associated with a significant increase of the S‐adenosylhomocysteine (SAH)/S‐adenosylmethionine ratio, and reduced DNA methyltrasferases and hypomethylation of 5‐lipoxygenase DNA. In vitro studies confirmed these results and demonstrated that the mechanism involved in the Hcy‐dependent 5LO activation and amyloid β formation is DNA hypomethylation secondary to the elevated levels of SAH. Taken together these findings represent the first demonstration that Hcy directly influences 5LO expression levels and establish a previously unknown cross talk between these two pathways, which is highly relevant for AD pathogenesis. The discovery of such a novel link not only provides new mechanistic insights in the neurobiology of Hcy, but most importantly new therapeutic opportunities for the individuals bearing this risk factor for the disease. 相似文献
5.
Amyloid β‐induced astrogliosis is mediated by β1‐integrin via NADPH oxidase 2 in Alzheimer's disease 下载免费PDF全文
Ane Wyssenbach Tania Quintela Francisco Llavero Jose L. Zugaza Carlos Matute Elena Alberdi 《Aging cell》2016,15(6):1140-1152
Astrogliosis is a hallmark of Alzheimer′s disease (AD) and may constitute a primary pathogenic component of that disorder. Elucidation of signaling cascades inducing astrogliosis should help characterizing the function of astrocytes and identifying novel molecular targets to modulate AD progression. Here, we describe a novel mechanism by which soluble amyloid‐β modulates β1‐integrin activity and triggers NADPH oxidase (NOX)‐dependent astrogliosis in vitro and in vivo. Amyloid‐β oligomers activate a PI3K/classical PKC/Rac1/NOX pathway which is initiated by β1‐integrin in cultured astrocytes. This mechanism promotes β1‐integrin maturation, upregulation of NOX2 and of the glial fibrillary acidic protein (GFAP) in astrocytes in vitro and in hippocampal astrocytes in vivo. Notably, immunochemical analysis of the hippocampi of a triple‐transgenic AD mouse model shows increased levels of GFAP, NOX2, and β1‐integrin in reactive astrocytes which correlates with the amyloid β‐oligomer load. Finally, analysis of these proteins in postmortem frontal cortex from different stages of AD (II to V/VI) and matched controls confirmed elevated expression of NOX2 and β1‐integrin in that cortical region and specifically in reactive astrocytes, which was most prominent at advanced AD stages. Importantly, protein levels of NOX2 and β1‐integrin were significantly associated with increased amyloid‐β load in human samples. These data strongly suggest that astrogliosis in AD is caused by direct interaction of amyloid β oligomers with β1‐integrin which in turn leads to enhancing β1‐integrin and NOX2 activity via NOX‐dependent mechanisms. These observations may be relevant to AD pathophysiology. 相似文献
6.
Michio Hashimoto Hossain Md Shahdat Shinji Yamashita Masanori Katakura Yoko Tanabe Hironori Fujiwara Shuji Gamoh Teruo Miyazawa Hiroyuki Arai Toshio Shimada Osamu Shido 《Journal of neurochemistry》2008,107(6):1634-1646
We have previously reported that dietary docosahexaenoic acid (DHA) improves and/or protects against impairment of cognition ability in amyloid beta1‐40 (Aβ1‐40)‐infused Alzheimer’s disease (AD)‐model rats. Here, after the administration of DHA to AD model rats for 12 weeks, the levels of Aβ1‐40, cholesterol and the composition of fatty acids were investigated in the Triton X100‐insoluble membrane fractions of their cerebral cortex. The effects of DHA on the in vitro formation and kinetics of fibrillation of Aβ1‐40 were also investigated by thioflavin T fluorescence spectroscopy, transmission electron microscopy and fluorescence microscopy. Dietary DHA significantly decreased the levels of Aβ1‐40, cholesterol and saturated fatty acids in the detergent insoluble membrane fractions of AD rats. The formation of Aβ fibrils was also attenuated by their incubation with DHA, as demonstrated by the decreased intensity of thioflavin T‐derived fluorescence and by electron micrography. DHA treatment also decreased the intensity of thioflavin fluorescence in preformed‐fibril Aβ peptides, demonstrating the anti‐amyloidogenic effects of DHA. We then investigated the effects of DHA on the levels of oligomeric amyloid that is generated during its in vitro transformation from monomers to fibrils, by an anti‐oligomer‐specific antibody and non‐reducing Tris‐Glycine gradient (4–20%) gel electrophoresis. DHA concentration‐dependently reduced the levels of oligomeric amyloid species, suggesting that dietary DHA‐induced suppression of in vivo Aβ1‐40 aggregation occurs through the inhibitory effect of DHA on oligomeric amyloid species. 相似文献
7.
Rona Limor Marielle Kaplan Orly Sharon Esther Knoll Michal Naidich Gary Weisinger Shlomo Keidar Naftali Stern 《Journal of cellular biochemistry》2009,108(5):1203-1210
Several lines of evidence suggest that aldosterone excess may have detrimental effects in the cardiovascular system, independent of its interaction with the renal epithelial cells. Here we examined the possibility that aldosterone modulates 12‐ and/or 15‐lipoxygenase (LO) expression/activity in human vascular smooth muscle cells (VSMC), in vitro, thereby potentially contributing to both vascular reactivity and atherogenesis. Following 24 h treatment of VSMC with aldosterone (1 nmol/L), there was a ~2‐fold increase in the generation rate of 12 hydroxyeicosatetraenoic acid (12‐HETE), 70% increase in platelet type 12‐LO mRNA expression (P < 0.001) along with a ~3‐fold increase in 12‐LO protein expression, which were blocked by the mineralocorticoid receptor (MR) antagonists spironolactone (100 nmol/L) and eplerelone (100 nmol/ml). Additionally, aldosterone (1 nmol/L; 24 h) increased the production of 15‐HETE (50%; P < 0.001) and the expression of 15‐LO type 2 mRNA (50%; P < 0.05) (in VSMC). Aldosterone also increased the 12‐ and 15‐LO type 2 mRNA expression in a line of human aortic smooth muscle cells (T/G HA‐VSMC) (60% and 50%, respectively). Aldosterone‐induced 12‐ and 15‐LO type 2 mRNA expressions were blocked by the EGF‐receptor antagonist AG 1478 and by the MAPK‐kinase inhibitor UO126. Aldosterone‐treated VSMC also showed increased LDL oxidation, (~2‐fold; P < 0.001), which was blocked by spironolactone. In conclusion, aldosterone increased 12‐ and 15‐LO expression in human VSMC, in association with increased 12‐ and 15‐HETE generation and enhanced LDL oxidation and may directly augment VSMC contractility, hypertrophy, and migration through 12‐HETE and promote LDL oxidation via the pro‐oxidative properties of these enzymes. J. Cell. Biochem. 108: 1203–1210, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
8.
Multiple mechanisms of dimethyl fumarate in amyloid β‐induced neurotoxicity in human neuronal cells 下载免费PDF全文
Michela Campolo Giovanna Casili Marika Lanza Alessia Filippone Irene Paterniti Salvatore Cuzzocrea Emanuela Esposito 《Journal of cellular and molecular medicine》2018,22(2):1081-1094
Alzheimer disease (AD) is characterized by a complex heterogeneity of pathological changes, and any therapeutic approach categorically requires a multi‐targeted way. It has been demonstrated that together with the hallmarks of the disease such as neurofibrillary tangles and senile plaques, oxidative and inflammatory stress covered an important role. Dimethyl fumarate (DMF) is an orally bioavailable methyl ester of fumaric acid and activator of Nrf2 with potential neuroprotective and immunomodulating activities. Therefore, the aim of the present work was to evaluate the potential beneficial effects of DMF, compared with its active metabolite monomethyl fumarate (MMF) (both at 30 μM) in an in vitro Alzheimer's model using SH‐SY5Y human neuroblastoma cell lines stimulated with amyloid‐beta (Aβ). Moreover, the effect of DMF, compared with MMF, was evaluate by an ex vivo model using organotypic hippocampal slice cultures stimulated with Aβ1‐42 (1 μg/ml), to better understand its action in a pathological setting. In both models, DMF pre‐treatment (30 μM) preserved cellular viability from Aβ stimulation, reducing tau hyper‐phosphorylation, much more efficiently then MMF (30 μM). Moreover, DMF was able to induce an activation of manganese superoxide dismutase (MnSOD) and heme‐oxygenase‐1 (HO‐1), decreasing the severity of oxidative stress. Our results showed important multi‐protective effects of DMF pre‐treatment from Aβ stimulation both in in vitro and ex vivo models, highlighting an Nrf2/NF‐κB‐dependent mechanism, which could provide a valuable support to the therapies for neurodegenerative diseases today. 相似文献
9.
Xiaolei Zhu Lan Ye Huiming Ge Ling Chen Nan Jiang Lai Qian Lingling Li Rong Liu Shen Ji Su Zhang Jiali Jin Dening Guan Wei Fang Renxiang Tan Yun Xu 《Aging cell》2013,12(1):85-92
Increasing evidence demonstrates that amyloid beta (Aβ) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Aβ is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase‐inhibitory and anti‐oxidative in H2O2‐treated PC12 cells. In this study, we reported that HopA might bind to Aβ1–42 directly and inhibit the Aβ1–42 aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Aβ1–42 and Aβ‐binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long‐term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD. 相似文献
10.
12/15 Lipoxygenase (12/15LO) protein levels and activity are increased in pathologically affected regions of Alzheimer's disease (AD) brains, compared with controls. Its metabolic products are elevated in cerebrospinal fluid of patients with AD and individuals with mild cognitive impairment, suggesting that this enzyme may be involved early in AD pathogenesis. Herein, we investigate the effect of pharmacologic inhibition of 12/15LO on the amyloid beta precursor protein (APP) metabolism. To this end, we used CHO and N2A cells stably expressing human APP with the Swedish mutant, and two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC. Our results demonstrated that both drugs dose-dependently reduced Abeta formation without affecting total APP levels. Interestingly, in the same cells we observed a significant reduction in secreted (s)APPbeta and beta-secretase (BACE), but not sAPPalpha and ADAM10 protein levels. Together, these data show for the first time that this enzymatic pathway influences Abeta formation whereby modulating the BACE proteolytic cascade. We conclude that specific pharmacologic inhibition of 12/15LO could represent a novel therapeutic target for treating or preventing AD pathology in humans. 相似文献
11.
Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase 下载免费PDF全文
Alterations of glucose metabolism have been observed in Alzheimer's disease (AD) brain. Previous studies showed that glucose deprivation increases amyloidogenesis via a BACE‐1‐dependent mechanism. However, no data are available on the effect that this condition may have on tau phosphorylation. In this study, we exposed neuronal cells to a glucose‐free medium and investigated the effect on tau phosphorylation. Compared with controls, cells incubated in the absence of glucose had a significant increase in tau phosphorylation at epitopes Ser202/Thr205 and Ser404, which was associated with a selective activation of the P38 mitogen‐activated protein kinase. Pharmacological inhibition of this kinase prevented the increase in tau phosphorylation, while fluorescence studies revealed its co‐localization with phosphorylated tau. The activation of P38 was secondary to the action of the apoptosis signal‐regulating kinase 1, as its down‐regulation prevented it. Finally, glucose deprivation induced cell apoptosis, which was associated with a significant increase in both caspase 3 and caspase 12 active forms. Taken together, our studies reveal a new mechanism whereby glucose deprivation can modulate AD pathogenesis by influencing tau phosphorylation and suggest that this pathway may be a new therapeutic target for AD. 相似文献
12.
Jing Zhao Yimin Feng Hui Yan Yangchao Chen Jinlan Wang Balvin Chua Charles Stuart Deling Yin 《Journal of cellular and molecular medicine》2014,18(8):1562-1570
Stem‐cell antigen 1–positive (Sca‐1+) cardiac stem cells (CSCs), a vital kind of CSCs in humans, promote cardiac repair in vivo and can differentiate to cardiomyocytes with 5′‐azacytizine treatment in vitro. However, the underlying molecular mechanisms are unknown. β‐arrestin2 is an important scaffold protein and highly expressed in the heart. To explore the function of β‐arrestin2 in Sca‐1+ CSC differentiation, we used β‐arrestin2–knockout mice and overexpression strategies. Real‐time PCR revealed that β‐arrestin2 promoted 5′‐azacytizine‐induced Sca‐1+ CSC differentiation in vitro. Because the microRNA 155 (miR‐155) may regulate β‐arrestin2 expression, we detected its role and relationship with β‐arrestin2 and glycogen synthase kinase 3 (GSK3β), another probable target of miR‐155. Real‐time PCR revealed that miR‐155, inhibited by β‐arrestin2, impaired 5′‐azacytizine‐induced Sca‐1+ CSC differentiation. On luciferase report assay, miR‐155 could inhibit the activity of β‐arrestin2 and GSK3β, which suggests a loop pathway between miR‐155 and β‐arrestin2. Furthermore, β‐arrestin2‐knockout inhibited the activity of GSK3β. Akt, the upstream inhibitor of GSK3β, was inhibited in β‐arrestin2‐Knockout mice, so the activity of GSK3β was regulated by β‐arrestin2 not Akt. We transplanted Sca‐1+ CSCs from β‐arrestin2‐knockout mice to mice with myocardial infarction and found similar protective functions as in wild‐type mice but impaired arterial elastance. Furthermore, low level of β‐arrestin2 agreed with decreased phosphorylation of AKT and increased phophorylation of GSK3β, similar to in vitro findings. The β‐arrestin2/miR‐155/GSK3β pathway may be a new mechanism with implications for treatment of heart disease. 相似文献
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Alzheimer's disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders; amyloid plaques (AP) that contain amyloid β‐protein (Aβ) accumulate in AD, which is also characterized by tau phosphorylation. Epidemiological evidence has demonstrated that long‐term treatment with nonsteroidal anti‐inflammatory drugs (NSAIDs) markedly reduces the risk of AD by inhibiting the expression of cyclooxygenase 2 (COX‐2). Although the levels of COX‐2 and its metabolic product prostaglandin (PG)E2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown. Using human‐ or mouse‐derived glioblastoma and neuroblastoma cell lines as model systems, we delineated the signaling pathways by which COX‐2 mediates the reciprocal regulation of interleukin‐1β (IL‐1β) and Aβ between glial and neuron cells. In glioblastoma cells, COX‐2 regulates the synthesis of IL‐1β in a PGE2‐dependent manner. Moreover, COX‐2‐derived PGE2 signals the activation of the PI3‐K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF‐κB p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL‐1β synthesis. The secretion of IL‐1β from glioblastoma cells in turn stimulates the expression of COX‐2 in human or mouse neuroblastoma cells. Similar regulatory mechanisms were found for the COX‐2 regulation of BACE‐1 expression in neuroblastoma cells. More importantly, Aβ deposition mediated the inflammatory response of glial cells via inducing the expression of COX‐2 in glioblastoma cells. These findings not only provide new insights into the mechanisms of COX‐2‐induced AD but also initially define the therapeutic targets of AD. 相似文献
15.
Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL‐1β/NF‐κB pathway 下载免费PDF全文
Zuqiang Wang Junlan Huang Siru Zhou Fengtao Luo Wei Xu Quan Wang Qiaoyan Tan Liang chen Jun Wang Hangang Chen Lin Chen Yangli Xie Xiaolan Du 《Journal of cellular and molecular medicine》2017,21(12):3231-3243
The osteoarthritis (OA) progression is now considered to be related to inflammation. Anemonin (ANE) is a small natural molecule extracted from various kinds of Chinese traditional herbs and has been shown to inhibiting inflammation response. In this study, we examined whether ANE could attenuate the progression of OA via suppression of IL‐1β/NF‐κB pathway activation. Destabilization of the medial meniscus (DMM) was performed in 10‐week‐old male C57BL/6J mice. ANE was then intra‐articularly injected into joint capsule for 8 and 12 weeks. Human articular chondrocytes and cartilage explants challenged with interleukin‐1β (IL‐1β) were treated with ANE. We found that ANE delayed articular cartilage degeneration in vitro and in vivo. In particular, proteoglycan loss and chondrocyte hypertrophy were significantly decreased in ANE ‐treated mice compared with vehicle‐treated mice. ANE decreased the expressions of matrix metalloproteinase‐13 (MMP13), A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), collagen X (Col X) while increasing Aggrecan level in murine with DMM surgery. ANE treatment also attenuated proteoglycan loss in human cartilage explants treated with IL‐1β ex vivo. ANE is a potent protective molecule for OA; it delays OA progression by suppressing ECM loss and chondrocyte hypertrophy partially by suppressing IL‐1β/NF‐κB pathway activation. 相似文献
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Ramona Belfiore Alexis Rodin Eric Ferreira Ramon Velazquez Caterina Branca Antonella Caccamo Salvatore Oddo 《Aging cell》2019,18(1)
Accumulation of amyloid‐β (Aβ) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer’s disease (AD). After almost 15 years from their generation, 3xTg‐AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg‐AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed Aβ and tau load, neuroinflammation, and cognitive changes in 2‐, 6‐, 12‐, and 20‐month‐old female 3xTg‐AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had Aβ plaques in the caudal hippocampus at 6 months of age, while 100% of them had Aβ plaques in the hippocampus at 12 months of age. Cortical Aβ plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6‐month‐old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6‐month‐old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD‐like pathology in female 3xTg‐AD mice, and will facilitate the design of future studies using these mice. 相似文献
18.
X. Zhu Y. Wang O. Ogawa H. G. Lee A. K. Raina H. Fujioka S. Shimohama C. S. Atwood R. B. Petersen G. Perry M. A. Smith 《Journal of neurochemistry》2002,81(Z1):76-76
The mechanisms underlying neuronal degeneration in Alzheimer's disease (AD) are very controversial and none more so than whether apoptosis plays a role. Although neurons in AD face a wide assortment of apoptogenic stimuli, the temporal dichotomy between the acuteness of apoptosis vs. the chronicity of AD suggests that apoptosis should be extremely rare in AD. In this regard, survival factor(s) must be involved. In this study, we investigated Bcl‐w, a pro‐survival member of the Bcl‐2 family. Although expressed at low levels in brains of control cases, Bcl‐w is significantly up‐regulated in AD as shown by both immunocytochemistry and immunoblot analysis. Astonishingly, increased Bcl‐w was found to be associated with neurofibrillary pathologies in AD, which was further demonstrated by an EM study. Since neuronal death in AD is thought to be triggered by increased production of amyloid‐β (Aβ), it was interesting to find that exposure of human M17 neuroblastoma cells to Aβ1–42 (1 nm ?10 μm ) dramatically up‐regulates Bcl‐w protein levels. Such increases may be a protective response that attenuates apoptotic processes. Consistent with this, transfected M17 cells overexpressing Bcl‐w were protected from both STS‐induced and Aβ‐induced apoptosis compared to vector‐transfected controls. Notably, both tau phosphorylation and p38 is inhibited in Bcl‐w transfected cells which may contribute to the neuroprotective role of Bcl‐w. Taken together, these set of in vitro and in vivo results suggest that Bcl‐w plays an important protective role in neurons in the AD brain. 相似文献
19.
Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20‐APP transgenic and wild‐type mice 下载免费PDF全文
20.
Marat Mukhtarov Anton Malkov Alan Alpár Giuseppe Tortoriello Catherine H. Botting Lívia Fülöp Alex A. Osypov Asla Pitkänen Heikki Tanila Tibor Harkany Yuri Zilberter 《Journal of neurochemistry》2013,125(1):157-171
Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid‐beta‐induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid‐β1–42 (Aβ1–42) induced aberrant network activity in wild‐type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA‐mediated current reversal potential. Aβ1–42 also impaired synaptic function and long‐term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3‐beta‐hydroxybutyrate, Aβ1–42 failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD‐related epilepsy phenotype. In the ex‐vivo slices, we found neuronal subpopulations with significantly depolarized resting and GABA‐mediated current reversal potentials, mirroring abnormalities we observed under acute Aβ1‐42 application. Ex‐vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild‐type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES‐enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD‐related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates. 相似文献