p-Cresol Sulfate Caused Behavior Disorders and Neurodegeneration in Mice with Unilateral Nephrectomy Involving Oxidative Stress and Neuroinflammation
Chiao‐Yin SunJian‐Ri LiYayu WangShih‐Yi LinYen‐Chuan OuCheng‐Jui LinJiaan‐Der WangSu‐Lan LiaoChun‐Jung Chen
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Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases.A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neuroinflammation associated with neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter the expression of a plethora of inflammatory mediators. These factors, in turn, initiate or contribute to the development of neurodegenerative processes. Therefore, LPS is an important tool for the study of neuroinflammation associated with neurodegenerative diseases. However, the serotype, route of administration, and number of injections of this toxin induce varied pathological responses. Thus, here, we review the use of LPS in various models of neurodegeneration as well as discuss the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the neurodegenerative process.
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The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs
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Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases. However, the mechanisms modulating these processes in different diseases remain incompletely understood. Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system (CNS). Lgals3 encodes galectin-3 (Gal3), a β-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases. While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases, recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. In this review, we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases. We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.
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Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.
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Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19.Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity.Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
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AMA Pluta R, Bogucka-Kocka A, Ułamek-Kozioł M, et al. Review paperNeurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?. Folia Neuropathologica. 2015;53(2):89-99. doi:10.5114/fn.2015.52405. APA Pluta, R., Bogucka-Kocka, A., Ułamek-Kozioł, M., Furmaga-Jabłońska, W., Januszewski, S., & Brzozowska, J. et al. (2015). Review paperNeurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?. Folia Neuropathologica, 53(2), 89-99. https://doi.org/10.5114/fn.2015.52405 Chicago Pluta, Ryszard, Anna Bogucka-Kocka, Marzena Ułamek-Kozioł, Wanda Furmaga-Jabłońska, Sławomir Januszewski, Judyta Brzozowska, and Mirosław Jabłoński et al. 2015. "Review paperNeurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?". Folia Neuropathologica 53 (2): 89-99. doi:10.5114/fn.2015.52405. Harvard Pluta, R., Bogucka-Kocka, A., Ułamek-Kozioł, M., Furmaga-Jabłońska, W., Januszewski, S., Brzozowska, J., Jabłoński, M., and Kocki, J. (2015). Review paperNeurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?. Folia Neuropathologica, 53(2), pp.89-99. https://doi.org/10.5114/fn.2015.52405 MLA Pluta, Ryszard et al. "Review paperNeurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?." Folia Neuropathologica, vol. 53, no. 2, 2015, pp. 89-99. doi:10.5114/fn.2015.52405. Vancouver Pluta R, Bogucka-Kocka A, Ułamek-Kozioł M, Furmaga-Jabłońska W, Januszewski S, Brzozowska J et al. Review paperNeurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?. Folia Neuropathologica. 2015;53(2):89-99. doi:10.5114/fn.2015.52405.
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Purpose of review Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes ? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19. Recent findings Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity. Summary Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
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