Objectives: Increases in astrocytes and one of their markers, glial fibrillary acidic protein (GFAP) have been reported in the brains of patients with Alzheimer’s disease (AD). N-3 polyunsaturated fatty acids (PUFA) modulate neuroinflammation in animal models; however, their effect on astrocytes is unclear.
Methods: Fat-1 mice and their wildtype littermates were fed either a fish oil diet or a safflower oil diet deprived of n-3 PUFA. At 12 weeks, mice underwent intracerebroventricular infusion of amyloid-β 1-40. Astrocyte phenotype in the hippocampus was assessed at baseline and 10 days post-surgery using immunohistochemistry with various microscopy and image analysis techniques.
Results: GFAP increased in all groups in response to amyloid-β, with a greater increase in fish oil-fed mice than either fat-1 or wildtype safflower oil-fed mice. Astrocytes in this group were also more hypertrophic, suggesting increased activation. Both fat-1- and fish oil-fed mice had greater increases in branch number and length in response to amyloid-β infusion than wildtype safflower animals.
Conclusion: Fish oil feeding, and to a lesser extent the fat-1 transgene, enhances the astrocyte activation phenotype in response to amyloid-β 1-40. Astrocytes in mice fed fish oil were more activated in response to amyloid-β than in fat-1 mice despite similar levels of hippocampal n-3 PUFA, which suggests that other fatty acids or dietary factors contribute to this effect. 相似文献
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6‐hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH‐positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies. 相似文献
In the past decade, numerous studies have demonstrated the close relationship between gut microbiota and the occurrence and development of Alzheimer’s disease (AD). However, the specific mechanism is still unclear. Both the neuroinflammation and systemic inflammation serve as the key hubs to accelerate the process of AD by promoting pathology and damaging neuron. What's more, the gut microbiota is also crucial for the regulation of inflammation. Therefore, this review focused on the role of gut microbiota in AD through inflammatory pathways. Firstly, this review summarized the relationship and interaction among gut microbiota, inflammation, and AD. Secondly, the direct and indirect regulatory effects of gut microbiota on AD through inflammatory pathways were described. These effects were mainly mediated by the component of the gut microbiota (lipopolysaccharides (LPS) and amyloid peptides), the metabolites of bacteria (short-chain fatty acids, branched amino acids, and neurotransmitters) and functional by-products (bile acids). In addition, potential treatments (fecal microbiota transplantation, antibiotics, probiotics, prebiotics, and dietary interventions) for AD were also discussed through these mechanisms. Finally, according to the current research status, the key problems to be solved in the future studies were proposed. 相似文献
Sepsis-associated encephalopathy (SAE) increases not only morbidity and mortality but has been associated with long-lasting mental impairment after hospital discharge in septic patients. Recently, studies have shown that these mental impairments are caused by infection-induced neuroinflammation. However, the role of T cells in the pathogenesis of SAE and mental impairments remains unclear. Thus, in this study, we aimed to clarify how immune cells, especially T cells, influence the development and recovery of these disorders. In the cecal slurry (CS)-induced septic mouse model, we performed three different kinds of behavioral tests, open-field test, marble burying test, and forced swimming test, and observed anxiety-like behavior in septic mice. Additionally, increased interleukin (IL)-1β and IL-6 expression levels, and infiltration of neutrophils and T cells were examined in the brain of septic mice, 10 days after sepsis onset. Twenty days after sepsis onset, the septic mice could recover the number of astrocytes. At day 30, expression levels of IL-1β and tumor necrosis factor (TNF)-α returned to normal levels in the cerebral cortex of septic mice. Interestingly, resolution of neuroinflammation and alleviation of depression were delayed in septic mice treated with FTY720, which inhibits sphingosine-1-phosphate (S1P)-dependent lymphocyte egress from lymph nodes. On analyzing the brain T cells with or without FTY720 in septic mice, the FTY720 untreated mice presented increased regulatory T cells (Treg) and Th2 cells in the brain, whereas the FTY720 treated mice demonstrated increased Th17 in the brain at day 30. Furthermore, in FTY720 treated septic mice, the number of astrocytes in the cerebral cortex remained reduced at day 30. These results suggest that infiltrated Treg and Th2 cells contribute to the attenuation SAE and alleviate SAE-induce mental disorder by resolving neuroinflammation in the chronic phase of sepsis. 相似文献
CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults.Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [18F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions.Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships.Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate. 相似文献
Emerging evidence indicates an important role for neuroinflammation in depression. Brief maternal separation promotes resilience to depression in offspring, but relatively little is known about the effects of different durations of postpartum separation (PS) from offspring on anxiety and depressive-like behaviors in dams following immune challenge. Lactating C57BL/6J mice were subjected to no separation (NPS), brief PS (15 min/day, PS15) or prolonged PS (180 min/day, PS180) from postpartum day (PPD) 1 to PPD21 and then injected with lipopolysaccharide (LPS). Behavioral tests, including the open field test (OFT) and forced swimming test (FST), were carried out at 24 h after the injection. LPS resulted in anxiety and depressive-like behaviors in NPS dams and activated ionized calcium-binding adaptor molecule (Iba1), an important biomarker of microglia, in the hippocampus. However, compared with NPS + LPS dams, PS15 + LPS dams spent significantly more time in the center of the OFT (anxiety-like behavior) and exhibited lower immobility time in the FST (depressive-like behavior), which indicated a phenomenon of resilience. Furthermore, the activation of neuroinflammation was inhibited in PS15 dams. Specifically, levels of the Iba1 mRNA and protein were decreased, while the mRNA expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome/interleukin-18 (IL-18)/nuclear factor kappa-B (NF-κB) was decreased in the hippocampus. Furthermore, positive linear correlations were observed between microglial activation and LPS-induced depressive-like behaviors in dams. Collectively, the findings of this study confirm that brief PS from offspring promotes resilience to LPS immune challenge-induced behavioral deficits and inhibits neuroinflammation in dams separated from their offspring during lactation. 相似文献
Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca2+ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference. 相似文献