Enriched environment enhances ?-adrenergic signaling to prevent microglia inflammation by amyloid-?.
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PROVIDER: S-EPMC6127891 | BioStudies |
REPOSITORIES: biostudies
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Project description:Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble A? oligomers (oA?) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oA?-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNF?) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oA? extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oA?, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system.Environmental enrichment (EE) is a potential therapy to delay Alzheimer's disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human A? oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.
| S-EPMC5005718 | BioStudies
Project description:A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of ?2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid ?-protein (A?) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a ?-adrenergic agonist without EE were protected from hippocampal impairment by A? oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating ?-adrenoceptor signaling and mitigating synaptotoxicity of human A? oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral ?-adrenergic agonists to lessen the effects of A? accumulation during aging.
| S-EPMC3596823 | BioStudies
Project description:Microglia, the resident immune cells of the central nervous system (CNS), monitor the brain for disturbances of tissue homeostasis by constantly moving their fine processes. Microglia respond to tissue damage through activation of ATP/ADP receptors followed by directional process extension to the damaged area. A common feature of several neurodegenerative diseases is the loss of norepinephrine, which might contribute to the associated neuroinflammation. We carried out a high resolution analysis of the effects of norepinephrine (NE) on microglial process dynamics in acute brain slices from mice that exhibit microglia-specific enhanced green fluorescent protein expression. Bath application of NE to the slices resulted in significant process retraction in microglia. Analysis of adrenergic receptor expression with quantitative PCR indicated that resting microglia primarily express ?2 receptors but switch expression to ?2A receptors under proinflammatory conditions modeled by LPS treatment. Despite the differential receptor expression, NE caused process retraction in both resting and LPS-activated microglia cultured in the gelatinous substrate Matrigel in vitro. The use of subtype-selective receptor agonists and antagonists confirmed the involvement of ?2 receptors in mediating microglial process dynamics in resting cells and ?2A receptors in activated cells. Co-application of NE with ATP to resting microglia blocked the ATP-induced process extension and migration in isolated microglia, and ?2 receptor antagonists prolonged ATP effects in brain slice tissues, suggesting the presence of cross-talk between adrenergic and purinergic signaling in microglia. These data show that the neurotransmitter NE can modulate microglial motility, which could affect microglial functions in pathogenic situations of either elevated or reduced NE levels.
| S-EPMC3663549 | BioStudies
Project description:<h4>Background</h4>Reactive microglia are associated with ?-amyloid (A?) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A? deposits although they mainly exist in an "activated" state. Oligomeric A? (oA?), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A? (fA?). However, the role of the different A? forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.<h4>Results</h4>We demonstrated that A?(1-42) fibrils, not A?(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA?(1-42) not only attenuated fA?(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA?(1-42). Compared with the fA?(1-42) treatment, the oA?(1-42) treatment resulted in a rapid and transient increase in interleukin 1? (IL-1?) level and produced higher levels of tumor necrosis factor-? (TNF-?), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA?(1-42)-induced microglia was decreased by IL-1?, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-?B (NF-?B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA?-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA?(1-42) stimulation reduced the mRNA expression of CD36, integrin ?1 (Itgb1), and Ig receptor Fc?RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA?(1-42) or the inflammatory and oxidative milieu (IL-1?, LPS or t-BHP) significantly downregulated the fA?(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.<h4>Conclusion</h4>These results imply that A? oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of A? fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.
| S-EPMC3149591 | BioStudies
Project description:Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Abeta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Abeta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Abeta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Abeta plaque sites and impaired microglial Abeta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Abeta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.
2010-01-01 | S-EPMC2851853 | BioStudies
Project description:Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of ?2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of ?2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.
| S-EPMC6875777 | BioStudies
Project description:Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.
| S-EPMC6858573 | BioStudies
Project description:Aging is associated with increased central nervous system inflammation, in large part due to dysfunctional microglia. Environmental enrichment (EE) provides a model for studying the dynamics of lifestyle factors in the development of age-related neuroinflammation and microglial dysfunction. EE results in improvements in learning and memory, metabolism, and mental health in a variety of animal models. We recently reported that implementing EE in middle age promotes healthy aging. In the present study, we investigated whether EE influences microglial morphology, and whether EE is associated with changes in expression of microglial and neuroinflammatory markers. Inflammatory cytokines and MHC-II were reduced following 12-month EE in 10-month-old mice. Long-term EE for 7.5 months resulted in broad increases in Iba1 expression in hippocampus, hypothalamus, and amygdala detected by immunohistochemistry. Quantification of microglial morphology reveal both hypertrophy and ramification in these three brain regions, without increases in microglial cell density. These data indicate that long-term EE implemented in middle age results in a microglial state distinct from that of normal aging in standard laboratory housing, in specific brain regions, associated with reduced neuroinflammatory markers and improvement of systemic metabolism.
| S-EPMC6519992 | BioStudies
Project description:Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain (Ptn-Tg), we have found a positive correlation between iNos and Tnf? mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) ?/?, which is mainly expressed in the central nervous system. We aimed to test if RPTP?/? is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTP?/? (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-?B p65 expression, suggesting that RPTP?/? may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-?B p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTP?/? inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTP?/? plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.
| S-EPMC7679445 | BioStudies
Project description:BACKGROUND:Ischemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on ?2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in ?2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM ?2-adrenergic receptors to post-stroke neuroinflammation. METHODS:To investigate the effects of ?2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the ?2-adrenergic receptor agonist clenbuterol to mice 3?h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3?days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the ?2-adrenergic receptor from microglia and monocyte-lineage cells. RESULTS:We report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3?days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the ?2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of ?2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNF? and IL-10 in peri-infarct tissue, while stimulation of ?2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNF? and IL-10 expression. CONCLUSIONS:We identified ?2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased ?2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished ?2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The ?2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.
| S-EPMC6540436 | BioStudies