Glia Proinflammatory Cytokine Upregulation as a Therapeutic Target for Neurodegenerative Diseases: Function‐Based and Target‐Based Discovery Approaches

Eldik, Linda J. Van; Thompson, Wendy L.; Ranaivo, Hantamalala Ralay; Behanna, Heather A.; Watterson, D. Martin

doi:10.1016/s0074-7742(07)82015-0

Cited by 130 publications

(99 citation statements)

References 77 publications

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“…In addition, the transcriptome of the hMSCs changed in response to the ischemic environment. The results were confirmed by assays for immune-related cytokines (12)(13)(14)(15)(16)(17).…”

supporting

confidence: 53%

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Ohtaki

Ylöstalo

Foraker

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

369

297

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Human mesenchymal stromal cells (hMSCs) were injected into the hippocampus of adult mice 1 day after transient global ischemia. The hMSCs both improved neurologic function and markedly decreased neuronal cell death of the hippocampus. Microarray assays indicated that ischemia up-regulated 586 mouse genes. The hMSCs persisted for <7 days, but they down-regulated >10% of the ischemia-induced genes, most of which were involved in inflammatory and immune responses. The hMSCs also upregulated three mouse genes, including the neuroprotective gene Ym1 that is expressed by activated microglia/macrophages. In addition, the transcriptomes of the hMSC changed with upregulation of 170 human genes and down-regulation of 54 human genes. Protein assays of the hippocampus demonstrated increased expression in microglia/macrophages of Ym1, the cell survival factor insulin-like growth factor 1, galectin-3, cytokines reflective of a type 2 T cell immune bias, and the major histocompatibility complex II. The observed beneficial effects of hMSCs were largely explained by their modulation of inflammatory and immune responses, apparently by alternative activation of microglia and/or macrophages.inflammation ͉ mesenchymal stromal cells ͉ microglia ͉ mesenchymal stem cells O bservations in rodent and primate models suggest that a potential therapy for ischemia of the central nervous system is the administration of the adult stem/progenitor cells from bone marrow referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) (1-3). Administration of MSCs also produced beneficial effects in animal models for neurodegenerative diseases, such as Parkinson's disease, experimental autoimmune encephalomyelitis, and amyotrophic lateral sclerosis (2-5). MSCs initially attracted interest for their ability to differentiate into multiple cellular phenotypes in culture and in vivo (1-7). However, recent observations indicate that only small numbers of the cells engraft into most injured tissues, and they disappear quickly (2-5, 8-10). When human MSCs (hMSCs) were injected into the dentate gyrus (DG) of the hippocampus in adult immunodeficient (ID) mice, most of the cells disappeared within 1 week, but they enhanced proliferation, migration, and neural differentiation of the endogenous neural stem cells (8). These and related observations have focused attention on the paracrine effects of MSCs (2, 3, 11). However, it has not been established whether the beneficial effects of MSCs in ischemic models of brain injury are explained by enhanced neurogenesis (8) or by neuroprotection.Experiments here were performed in a mouse model of global ischemia to assess the neuroprotective effects of hMSCs. Administration of hMSCs 1 day after transient common carotid artery occlusion (tCCAO) improved neurologic function and decreased the delayed neuronal cell death of the hippocampus. Surveys with microarrays indicated that the hMSCs decreased expression of many of the mouse genes that were induced by ischemia and that were involved in inflamma...

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“…In addition, the transcriptome of the hMSCs changed in response to the ischemic environment. The results were confirmed by assays for immune-related cytokines (12)(13)(14)(15)(16)(17).…”

supporting

confidence: 53%

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Ohtaki

Ylöstalo

Foraker

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

369

297

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“…38 However, in AD, glial inflammation is a chronic phenomenon, particularly around protein aggregates, where endogenous TNFα levels are presumably constantly high and may over-stimulate receptors, thus causing functional uncoupling. 68,70,71 At present, the functional significance of this defect is not established. However, one can speculate that a reduced astrocytic glutamate input to neurons may result in weakened connectivity…”

Section: Astrocyte Signaling In Pathologymentioning

confidence: 99%

“…Furthermore, astrocytic Ca 2+ variations appear to be critical also for the release of neurotoxic concentrations of the gliotransmitter glutamate initiated by high levels of TNFα. 38 Because this cytokine is highly represented in the CNS of AD patients and transgenic mice, 67,68,70,71 it is plausible to hypothesize that such process may be relevant also for AD-linked neurodamaging events. Our group tested this hypothesis using the PDAPP mice, a transgenic model of AD.…”

Section: Astrocyte Signaling In Pathologymentioning

confidence: 99%

“…66,67 In the brain of both AD subjects and animal models, reactive microglia and astrocytes produce high levels of pro-inflammatory cytokines that were proposed to exacerbate neuronal damage. [68][69][70][71] As the disease progresses, synapse loss and neuronal cell death become prominent, with the consequent shrinkage of the affected areas, i.e., the entorhinal cortex and the hippocampus. Amyloid plaques mostly consist of aggregated amyloid β (Aβ) peptide generated by the sequential proteolitic cleavages of the amyloid precursor protein (APP) via β-and γ-secretase enzymes.…”

Section: Alzheimer Diseasementioning

confidence: 99%

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Astrocyte signaling and neurodegeneration

Brambilla

Martorana

Rossi

2013

Prion

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“…Microglia activated in vitro induce the expression of proinflammatory cytokines, including IL-6, IL-8, TNF-a, reactive oxygen/nitrogen species, and chemokines, all of which are known to cause neuronal damage (Van Eldik et al, 2007;Zaheer et al, 2008;Fernández et al, 2013). Studies on brain tissue derived from patients with AD have shown that CB2 modulates hippocampal function in the context of AD pathology (Benito et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-139 modulates Alzheimer’s-associated pathogenesis in SAMP8 mice by targeting cannabinoid receptor type 2

Tang

Bao

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Alzheimer's disease (AD) is a neurodegenerative disorder, and is the most common type of dementia in the elderly population. Growing evidence indicates that microRNAs (miRNAs) play a crucial role in neuroinflammation associated with AD progression. In this study, we analyzed the expression of microRNA-139 (miR-139) as well as the learning and memory function in AD. We observed that the miR-139 expression was significantly higher in the hippocampus of aged senescence accelerated mouse prone 8 (SAMP8) mice (2.92 ± 0.13) than in the control mice (1.49 ± 0.08). Likewise, the overexpression of miR-139 by means of hippocampal injection impaired the hippocampus-dependent learning and memory formation. In contrast, the downregulation of miR-139 in mice improved learning and memory function in the mice. The level of cannabinoid receptor type 2 (CB2), a potential target gene of miR-139, was inversely correlated with the miR-139 expression in primary hippocampal cells. Furthermore, we demonstrated that miR-139 inversely modulated the responses to proinflammatory stimuli. Together, our findings demonstrate that miR- 139 exerts a pathogenic effect in AD by modulating CB2-meditated neuroinflammatory processes.

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Glia Proinflammatory Cytokine Upregulation as a Therapeutic Target for Neurodegenerative Diseases: Function‐Based and Target‐Based Discovery Approaches

Cited by 130 publications

References 77 publications

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Astrocyte signaling and neurodegeneration

MicroRNA-139 modulates Alzheimer’s-associated pathogenesis in SAMP8 mice by targeting cannabinoid receptor type 2

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