Plasma dilution improves cognition and attenuates neuroinflammation in old mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Mehdipour M
PROVIDER: S-EPMC8050203 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Alzheimer's disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling-more specifically, the leukotriene receptors-has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.
| S-EPMC7967180 | biostudies-literature
Project description:BACKGROUND:Trovafloxacin is a broad-spectrum antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels. Panx1 channels are important conduits for the adenosine triphosphate (ATP) release from live and dying cells that enhances the inflammatory response of immune cells. Elevated extracellular levels ATP released upon injury activate purinergic pathways in inflammatory cells that promote migration, proliferation, phagocytosis, and apoptotic signals. Here, we tested whether trovafloxacin administration attenuates the neuroinflammatory response and improves outcomes after brain trauma. METHODS:The murine controlled cortical impact (CCI) model was used to determine whether in vivo delivery of trovafloxacin has anti-inflammatory and neuroprotective actions after brain trauma. Locomotor deficit was assessed using the rotarod test. Levels of tissue damage markers and inflammation were measured using western blot, qPCR, and immunofluorescence. In vitro assays were used to evaluate whether trovafloxacin blocks ATP release and cell migration in a chemotactic-stimulated microglia cell line. RESULTS:Trovafloxacin treatment of CCI-injured mice significantly reduced tissue damage markers and improved locomotor deficits. In addition, trovafloxacin treatment significantly reduced mRNA levels of several pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?), which correlates with an overall reduction in the accumulation of inflammatory cell types (neutrophils, microglia/macrophages, and astroglia) at the injury zone. To determine whether trovafloxacin exerted these effects by direct action on immune cells, we evaluated its effect on ATP release and cell migration using a chemotactic-stimulated microglial cell line. We found that trovafloxacin significantly inhibited both ATP release and migration of these cells. CONCLUSION:Our results show that trovafloxacin administration has pronounced anti-inflammatory and neuroprotective effects following brain injury. These findings lay the foundation for future studies to directly test a role for Panx1 channels in pathological inflammation following brain trauma.
| S-EPMC5812039 | biostudies-literature
Project description:This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.
| S-EPMC9398900 | biostudies-literature
Project description:BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive abilities and memory leading to dementia. Electroacupuncture (EA) is a complementary alternative medicine approach, applying an electrical current to acupuncture points. In clinical and animal studies, EA causes cognitive improvements in AD and vascular dementia. However, EA-induced changes in cognition and microglia-mediated amyloid ? (A?) degradation have not been determined yet in AD animals. Therefore, this study investigated the EA-induced molecular mechanisms causing cognitive improvement and anti-inflammatory activity in five familial mutation (5XFAD) mice, an animal model of AD. METHODS:5XFAD mice were bilaterally treated with EA at the Taegye (KI3) acupoints three times per week for 2 weeks. To evaluate the effects of EA treatment on cognitive functions, novel object recognition and Y-maze tests were performed with non-Tg, 5XFAD (Tg), and EA-treated 5XFAD (Tg + KI3) mice. To examine the molecular mechanisms underlying EA effects, western blots, immunohistochemistry, and micro-positron emission tomography scans were performed. Furthermore, we studied synapse ultrastructures with transmission electron microscopy and used electrophysiology to investigate EA effects on synaptic plasticity in 5XFAD mice. RESULTS:EA treatment significantly improved working memory and synaptic plasticity, alleviated neuroinflammation, and reduced ultrastructural degradation of synapses via upregulation of synaptophysin and postsynaptic density-95 protein in 5XFAD mice. Furthermore, microglia-mediated A? deposition was reduced after EA treatment and coincided with a reduction in amyloid precursor protein. CONCLUSIONS:Our findings demonstrate that EA treatment ameliorates cognitive impairment via inhibition of synaptic degeneration and neuroinflammation in a mouse model of AD.
| S-EPMC6909515 | biostudies-literature
Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging associated frailty may preclude physical activity. AMP-activated protein kinase (AMPK) is a transcriptional regulator important for muscle physiology. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (2-month-old), aged (23-month-old) C57Bl/6 mice, and transgenic mice with muscle-specific mutated AMPK alpha-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3 to 14 days and tested in the Morris water maze, rotarod and open field. Improved water maze performance and motor function was observed, albeit at longer duration of administration, in aged (14 days AICAR) than young (3 days AICAR) mice. In the AMPKDN mice, the compound did not enhance behavior, providing support for a muscle mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus genes relevant to neuronal development and plasticity were enriched. Altogether, endurance related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. Key words: Skeletal Muscle, Brain, Exercise, AMPK, Learning and Memory, Morris water maze 23-month old female C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were housed under standard conditions, 3 mice per cage, with food and water ad libitum. Mice were injected intraperitoneally with 5-Aminoimidazole-4-carboxamide-1-a-D-ribofuranoside (AICAR, Toronto Research Chemicals Inc., Canada) dissolved in saline, 500 mg/kg/day for 3 (ACR3), 7 (ACR7) or 14 (ACR14) days or saline vehicle, for 3 (CTR) days. Thirty-three days after the final injection animals were deeply anesthetized with isofluorane and perfused transcardially with 0.9% NaCl solution. The gastrocnemius muscle and Hippocampus were quickly removed, frozen on dry ice and stored at M-bM-^HM-^R80 M-BM-0C for RNA isolation and microarray analysis.
2014-01-17 | E-GEOD-50873 | biostudies-arrayexpress
Project description:Traumatic brain injury (TBI) is a major cause of mortality and long-term disability around the world. Even mild to moderate TBI can lead to lifelong neurological impairment due to acute and progressive neurodegeneration and neuroinflammation induced by the injury. Thus, the discovery of novel treatments which can be used as early therapeutic interventions following TBI is essential to restrict neuronal cell death and neuroinflammation. We demonstrate that orally administered N-acetyl-L-leucine (NALL) significantly improved motor and cognitive outcomes in the injured mice, led to the attenuation of cell death, and reduced the expression of neuroinflammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice. Our data indicate that partial restoration of autophagy flux mediated by NALL may account for the positive effect of treatment in the injured mouse brain. Taken together, our study indicates that treatment with NALL would be expected to improve neurological function after injury by restricting cortical cell death and neuroinflammation. Therefore, NALL is a promising novel, neuroprotective drug candidate for the treatment of TBI.
| S-EPMC8084982 | biostudies-literature
Project description:Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti-inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV-2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS-induced M1 BV-2 microglia, also the inflammatory secretion phenotype of M1 BV-2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK-/mTOR-mediated autophagic flux stimulation.
| S-EPMC5783886 | biostudies-other
Project description:BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and impaired neurogenesis. Urolithin A (UA), a gut-microbial metabolite of ellagic acid, has been reported to exert anti-inflammatory effects in the brain. However, it is unknown whether UA exerts its properties of anti-inflammation and neuronal protection in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD.MethodsMorris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia, Aβ deposition, and neurogenesis. The expression of inflammatory mediators were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The modulating effects of UA on cell signaling pathways were assayed by Western blotting.ResultsWe demonstrated that UA ameliorated cognitive impairment, prevented neuronal apoptosis, and enhanced neurogenesis in APP/PS1 mice. Furthermore, UA attenuated Aβ deposition and peri-plaque microgliosis and astrocytosis in the cortex and hippocampus. We also found that UA affected critical cell signaling pathways, specifically by enhancing cerebral AMPK activation, decreasing the activation of P65NF-κB and P38MAPK, and suppressing Bace1 and APP degradation.ConclusionsOur results indicated that UA imparted cognitive protection by protecting neurons from death and triggering neurogenesis via anti-inflammatory signaling in APP/PS1 mice, suggesting that UA might be a promising therapeutic drug to treat AD.
| S-EPMC6417212 | biostudies-literature
Project description:Alzheimer's Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients' cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination, exacerbating tau aggregation and AD pathology. Thereby, inhibiting USP11 function, via either blocking USP11 activity or lowering USP11 protein level, may serve as an effective therapeutic strategy against AD. Our research introduces IsoLiPro, a unique lithium isobutyrate-L-proline coordination compound, effectively lowers USP11 protein level and enhances tau ubiquitination in vitro. Additionally, long-term oral administration of IsoLiPro dramatically reduces total and phosphorylated tau levels in AD transgenic mice. Moreover, IsoLiPro also significantly lessens β-amyloid deposition and synaptic damage, improving cognitive functions in these animal models. These results indicate that IsoLiPro, as a novel small-molecule USP11 inhibitor, can effectively alleviate AD-like pathologies and improve cognitive functions, offering promise as a potential multi-targeting therapeutic agent against AD.
| S-SCDT-10_1038-S44321-024-00146-7 | biostudies-other
Project description:BackgroundGenetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS. These mutations cause a loss of PLP function leading to a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation promotes disease progression in these models, suggesting that pharmacological modulation of inflammation might ameliorate disease outcome.MethodsWe applied teriflunomide, an approved medication for relapsing-remitting MS targeting activated T-lymphocytes, in the drinking water (10 mg/kg body weight/day). Experimental long-term treatment of PLP mutant mice was non-invasively monitored by longitudinal optical coherence tomography and by rotarod analysis. Immunomodulatory effects were subsequently analyzed by flow cytometry and immunohistochemistry and treatment effects regarding neural damage, and neurodegeneration were assessed by histology and immunohistochemistry.ResultsPreventive treatment with teriflunomide attenuated the increase in number of CD8+ cytotoxic effector T cells and fostered the proliferation of CD8+ CD122+ PD-1+ regulatory T cells in the CNS. This led to an amelioration of axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the innermost retinal composite layer in longitudinal studies and ameliorated clinical outcome upon preventive long-term treatment. Treatment of immune-incompetent PLP mutants did not provide evidence for a direct, neuroprotective effect of the medication. When treatment was terminated, no rebound of neuroinflammation occurred and histopathological improvement was preserved for at least 75 days without treatment. After disease onset, teriflunomide halted ongoing axonal perturbation and enabled a recovery of dendritic arborization by surviving ganglion cells. However, neither neuron loss nor clinical features were ameliorated, likely due to already advanced neurodegeneration before treatment onset.ConclusionsWe identify teriflunomide as a possible medication not only for PMS but also for inflammation-related genetic diseases of the nervous system for which causal treatment options are presently lacking.
| S-EPMC6031103 | biostudies-literature