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11.
Exposure to the neurotropic parasite, Toxoplasma gondii, causes significant brain and behavioral anomalies in humans and other mammals. Understanding the cellular mechanisms of T. gondii-generated brain pathologies would aid the advancement of novel strategies to reduce disease. Complement factor C1q is part of a classic immune pathway that functions peripherally to tag and remove infectious agents and cellular debris from circulation. In the developing and adult brain, C1q modifies neuronal architecture through synapse marking and pruning. T. gondii exposure and complement activation have both been implicated in the development of complex brain disorders such as schizophrenia. Thus, it seems logical that mechanistically, the physiological pathways associated with these two factors are connected. We employed a rodent model of chronic infection to investigate the extent to which cyst presence in the brain triggers activation of cerebral C1q. Compared to uninfected mice, cortical C1q was highly expressed at both the RNA and protein levels in infected animals bearing a high cyst burden. In these mice, C1q protein localized to cytoplasm, adjacent to GFAP-labeled astrocytes, near degenerating cysts, and in punctate patterns along processes. In summary, our results demonstrated an upregulation of cerebral C1q in response to latent T. gondii infection. Our data preliminarily suggest that this complement activity may aid in the clearance of this parasite from the CNS and in so doing, have consequences for the connectivity of neighboring cells and synapses. 相似文献
12.
《Immunopharmacology and immunotoxicology》2013,35(4):393-399
AbstractContext: Neuroimmunological response is associated with neurodegeneration in the human substantia nigra (SN) in Parkinson’s disease (PD).Objective: To explore the possibility that the neurotoxin, 6-hydroxydopamine (6-OHDA), could be used as a tool in mice to understand the immune response in PD.Materials and methods: We employed unilateral administration of 6-OHDA into the mouse SN. At 1 week, 2 weeks and 4 weeks post-injection, we used immunohistochemistry for the markers Iba-1 and gp91PHOX to investigate activated microglia in the SN. To examine the adaptive immune response, we used immunohistochemistry for CD3-positive T-lymphocytes, CD45R-positive B-lymphocytes and anti-mouse immunoglobulin-G (IgG). Dopamine neuron loss was examined using immunohistochemistry for the dopamine neuron marker, tyrosine hydroxylase.Results: Compared to vehicle, 6-OHDA administration induced an intense IgG deposition in the SN as well as increased infiltration of both T- and B- lymphocytes into the injected side of the midbrain. The adaptive immune response was associated with extensive destruction of dopamine neurons and extensive microglial activation at every time point in the 6-OHDA groups.Conclusion: Our results suggest that 6-OHDA administration in mice can a potential tool for understanding mechanisms underlying adaptive immune activation-induced neurodegeneration in PD. 相似文献
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Antonello Fadda Antonio Di Renzo Francesco Martelli Dario Marangoni Anna Paola Batocchi Daniela Giannini Vincenzo Parisi Benedetto Falsini 《Clinical neurophysiology》2013,124(8):1652-1658
ObjectiveSustained pattern stimulation in normal subjects induces adaptive changes in pattern electroretinogram (PERG), an effect that has been interpreted as a response of glial cells and retinal ganglion cells (RGC). The aim of this study was to compare the effect in normal subjects and in multiple sclerosis patients without previous optic neuritis.MethodsPERGs were elicited by a 7.5 Hz pattern stimulus, presented continuously over 152 s. Response cycles were averaged in 20 packets of 60 events each and amplitude and phase of the 2nd harmonic response was measured. Adaptive changes are expressed as amplitude reduction over the full examination time.ResultsIn normal subjects PERG amplitude declined progressively to a plateau (dA = ?0.46 μV, SE = 0.09 μV); in patients the effect size was severely reduced (dA = ?0.20 μV, SE = 0.04 μV). No significant difference was found in mean amplitude.ConclusionsThe results show reduced RGC habituation in patients, suggesting an abnormal gain and sensitivity control in the inner retina, even in absence of clinical optic neuritis. Recent findings in astrocyte biology and indications drawn from a mathematical model point to a key role of glial cells in this process.SignificanceThe proposed methodology may have implications in the assessment of MS patients and in understanding the pathophysiology of neurological and retinal disorders. 相似文献
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目的 探讨移植胶质细胞源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)基因修饰的神经干细胞(neural stem cells,NSCs)对暂时性缺血性脑卒中大鼠的神经保护。 方法 用GDNF重组腺病毒载体转染新生大鼠NSCs(GDNF/NSCs),分化培养7 d后,行免疫细胞化学染色检测微管相关蛋白2(MAP2)。采用改良的插线法制作暂时性脑缺血再灌注模型,3 d后经脑室分别移植生理盐水、NSCs和GDNF/NSCs。于再灌注后1、2、3、5、7周末处死大鼠,行免疫组织化学染色观察移植细胞在脑内的神经元分化及星形胶质细胞在缺血区形成胶质界膜情况,行Luxol fast blue(LFB)染色显示神经纤维损伤情况。 结果 GDNF/NSCs体外分化为MAP2+细胞的比例显著高于NSCs的分化。移植细胞在脑内分化为MAP2+细胞,于再灌注第5周分化达高峰,GDNF/NSCs组于再灌注第3~7周,其MAP2+细胞显著高于NSCs组。各组缺血区由星形胶质细胞形成的血管胶质界膜存在不同程度的破坏,其连续性中断。对照组在各个时间点,血管胶质界膜损伤严重,完整性差,两细胞移植组,其胶质界膜随时间延长逐渐完整,GDNF/NSCs组早于NSCs组完善对胶质界膜的修复。此外,GDNF/NSCs组的神经纤维损伤修复优于NSCs组。 结论 GDNF/NSCs比NSCs对暂时性缺血性脑卒中大鼠模型有更好的神经保护作用,可能是与GDNF提高了NSCs在脑内的神经元分化,增强了NSCs对胶质界膜及神经纤维修复有关。 相似文献
17.
Adipose derived stem cells (ASC) differentiate into a Schwann cell (SC)-like phenotype but the signalling pathways mediating this are unknown. We hypothesised that notch might be involved, given its important role in regulating SC development. Rat ASC were differentiated using bFGF, PDGF, GGF-2 and forskolin. RT-PCR analysis showed that mRNA for notch-1 and notch-2 receptors and the notch responsive gene, hes-1, were expressed throughout the differentiation process whereas jagged-1 a notch ligand, and the hey-1 gene were markedly down-regulated. In contrast delta-1 was up-regulated with differentiation and was strongly expressed by rat primary SC. Treatment of ASC with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor which blocks notch signalling, had no effect on up-regulation of SC proteins S100 or GFAP during differentiation. Furthermore, when co-cultured with NG108-15 neurons, differentiated ASC cultures treated in the absence or presence of DAPT enhanced neurite outgrowth to similar levels. Differentiated ASC expressed PMP-22 but P0 was only present when co-cultured with dorsal root ganglia neurons. DAPT did not affect the expression of these myelin proteins. Thus, ASC express components of the notch signalling pathway but our studies suggest notch is unlikely to play a role in the neurotrophic activity and myelination capability of ASC differentiated into SC-like cells. 相似文献
18.
A lentivirally delivered photoactivatable GFP to assess continuity in the endoplasmic reticulum of neurones and glia 总被引:1,自引:0,他引:1
Vicky C. Jones José J. Rodríguez Alexei Verkhratsky Owen T. Jones 《Pflügers Archiv : European journal of physiology》2009,458(4):809-818
The endoplasmic reticulum (ER) is the largest intracellular membranous organelle. Functions of the ER are many and diverse,
which include various biosynthetic, transport and signalling roles, central to cellular physiology, such as the biosynthesis
of membrane and secretory proteins and the regulation of intracellular calcium. Its continuous lumen also serves as a highway
for the distribution of proteins and ions to different regions of the cell, independent of the cytosol. The ER is an excitable
organelle, capable of generating a regenerative wave of calcium release, which can propagate along the endomembrane throughout
the entire cell, serving as a system of intracelluar communication in polarised cells. Nowhere is this feature of ER function
more crucial than in neurones. The extremely polarised nature of nerve cells presents a unique challenge for the global co-ordination
of localised physiological events such as growth cone guidance and synaptic plasticity. Clearly, the physical continuity of
the neuronal ER lumen is central to its functionality as a conduit for communication. To further probe the continuity of ER
in neurones and glia, we developed LV-PA-pIN-KDEL, a photoactivatable analogue of our recently described vector LV-pIN-KDEL,
a lentivirally delivered ER-targeting soluble GFP. We demonstrate the ability of this vector to transduce astrocytes and neurones
in culture and in cortical explants. Furthermore, we exploit the photoactivatable attributes of the vector together with a
focal laser photoactivation protocol to reveal the continuous nature of the ER lumen in these cell types, presenting the first
direct evidence of an astrocytic ER luminal continuum and providing more data to support the existence of a single ER lumen
in neurones.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
19.
A major pathology of methamphetamine abuse is loss of dopaminergic function due to destruction of dopaminergic terminals, especially in the striatum. This process is accompanied by gliosis by astrocytes and microglia. Here, we evaluated the function of endogenous nociceptin/orphanin FQ in these events using nociceptin receptor (NOP) knockout mice. Wild-type and knockout mice were injected systemically either saline vehicle or 5 mg/kg methamphetamine four times interspersed by 2 h intervals. Three days later, brains were immunohistochemically processed to visualize methamphetamine-induced loss of tyrosine hydroxylase (as a marker of damage to dopamine terminals), glial fibrillary acidic protein (GFAP, as a marker of astrocytes), and ionized calcium-binding adapter molecule 1 (lba-1, as a marker of microglia) in the striatum. Methamphetamine treatment induced an approximately 80% loss of tyrosine hydroxylase-immunoreactivity, and this effect was mildly attenuated in NOP receptor knockout mice. There was a large increase (approximately 15-fold) in GFAP-immunoreactivity in methamphetamine-treated wild-type mice, which was almost two times larger still in NOP receptor knockout mice. In contrast, Iba-1 immunostaining was only modestly increased (approximately 30%) by methamphetamine treatment, and there were no difference between genotypes. Finally, there were no genotype-dependent differences in hyperthermic responses to methamphetamine. These results indicate that endogenous nociceptin/orphanin FQ exacerbates the neurotoxic effects of methamphetamine on striatal dopamine neurons, and suggests this is due in part to an astrocyte-mediated event. 相似文献
20.
In the present study, the influence of astrocyte alignment on the direction and length of regenerating neurites was examined in vitro. Astrocytes were experimentally manipulated by different approaches to create longitudinally aligned monolayers. When cultured on the aligned monolayers, dorsal root ganglion neurites grew parallel to the long axis of the aligned astrocytes and were significantly longer than controls. Engineered monolayers expressed linear arrays of fibronectin, laminin, neural cell adhesion molecule, and chondroitin sulfate proteoglycan that were organized parallel to one another, suggesting that a particular spatial arrangement of these molecules on the astrocyte surface may be necessary to direct nerve regeneration in vivo. In contrast, no bias in directional outgrowth was observed for neurites growing on unorganized monolayers. The results suggest that altering the organization of astrocytes and their scar-associated matrix at the lesion site may be used to influence the direction and the length of adjacent regenerating axons in the damaged brain and spinal cord. 相似文献