The role of microglia in prion diseases and possible therapeutic targets: a literature review

Melo, Ananda Sampaio Lamenha Falcão de; Lima, Juliana Louise Dias; Malta, Maria Carolina Silva; Marroquim, Natália França; Moreira, Álvaro Rivelli; Ladeia, Isabelle de Almeida; Cardoso, Fabrízio Dos Santos; Gonçalves, Daniel Buzaglo; Dutra, Bruna Guimarães; Santos, Júlio César Claudino dos

doi:10.1080/19336896.2021.1991771

Cited by 10 publications

(7 citation statements)

References 67 publications

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“…M1 phenotype microglia produce a large number of proinflammatory cytokines, including nitric oxide (NO), reactive oxidative species, TNF-α, IL-1β, IL-6, IFN-γ [38], during which the expression of the M1 marker CD16 and iNOS are upregulated. M2 phenotype microglia produce anti-inflammatory factors such as IL-4 and IL-10, during which the expression of the M2 marker CD206, TGF-β, and the metabolic or Arg-1 are upregulated [39–42]. In this study, the microglia marker Iba-1 and the M1 marker iNOS were colabelled in lumbar SDH, and their expression was significantly increased in LDH rats, while expression of the proinflammatory cytokines TNF-α was also increased but significantly decreased after electroacupuncture treatment.…”

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Electroacupuncture relieves chronic pain by promoting microglia M2 polarization in lumbar disc herniation rats

Yang

Zhu

et al. 2023

NeuroReport

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Electroacupuncture has an effective analgesia on chronic pain caused by lumbar disc herniation (LDH) clinically, however, the underlying mechanism is unclear. In this study, we investigated whether electroacupuncture alleviated pain in LDH model rats by inducing spinal microglia M2 polarization. We established a noncompression LDH rat model by implanting autologous caudal nucleus pulposus into L5/L6 nerve root. Electroacupuncture (30 min/day) treatment on the ipsilateral side was started on the 8th postoperative day, once a day for consecutive 7 days. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested for pain behavior. Western blotting was used to detect the protein expression in lumbar enlargement (L5/L6). Immunofluorescence was used to detect iNOS+/Iba-1+ and Arg-1+/Iba-1+ and CB2R+/Iba-1+ in lumbar enlargement (L5/L6). We show that PWT and PWL decreased in the LDH group while Iba-1, iNOS, and TNF-α expression increased significantly in lumbar spinal dorsal horn (SDH) after LDH surgery, and revealing that microglia were activated and polarized towards proinflammatory M1 phenotype. Electroacupuncture treatment significantly increased PWT and PWL while reducing Iba-1, iNOS, and TNF-α expression, interestingly, Arg-1 and IL-10 expression were significantly increased. Moreover, electroacupuncture treatment led to CB2 receptors on microglia upregulation, while NF-κB and p-NF-κB expression in lumbar SDH downregulation. Our study indicated that electroacupuncture may reduce nociceptive hyperalgesia by inhibiting microglia activation and microglia M1 polarization and promoting microglia M2 polarization in lumbar SDH of LDH rats, which may be caused by the activation of CB2 receptors on microglia and inhibition of NF-κB pathway in lumbar SDH.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Electroacupuncture relieves chronic pain by promoting microglia M2 polarization in lumbar disc herniation rats

Yang

Zhu

et al. 2023

NeuroReport

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“…Microglia made up the largest population of cells (99,756/147,536 = 67%) assigned in our library and are well described as particularly responsive to prion replication, taking on reactive phenotypes that can both exacerbate pathology through excess inflammatory signaling and can protect against disease through clearance of toxic PrP Sc [ 53 , 58 , 63 ]. As expected, altered microglial transcripts were involved in cytokine signaling, phagocytosis and microglial activation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Specific genes such as Il12b , Serpine1 , Jun , Ftl1 , Nav2 , Cd14 , Trim30a and Cd74 demarked some of the microglial subtypes—possibly serving as markers of functionally diverse microglial subsets. Therefore, the next steps will be to verify these microglial sub-populations throughout disease progression and to determine their relative contribution to the reported protective and detrimental properties of activated microglia during prion disease [ 53 , 58 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

Slota

Sajesh

Frost

et al. 2022

acta neuropathol commun

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Prion diseases are neurodegenerative disorders with long asymptomatic incubation periods, followed by a rapid progression of cognitive and functional decline culminating in death. The complexity of intercellular interactions in the brain is challenging to unravel and the basis of disease pathobiology remains poorly understood. In this study, we employed single cell RNA sequencing (scRNAseq) to produce an atlas of 147,536 single cell transcriptomes from cortex and hippocampus of mice infected with prions and showing clinical signs. We identified transcriptionally distinct populations and sub-populations of all the major brain cell-types. Disease-related transcription was highly specific to not only overarching cell-types, but also to sub-populations of glia and neurons. Most striking was an apparent decrease in relative frequency of astrocytes expressing genes that are required for brain homeostasis such as lipid synthesis, glutamate clearance, synaptic modulation and regulation of blood flow. Additionally, we described a spectrum of microglial activation states that suggest delineation of phagocytic and neuroinflammatory functions in different cell subsets. Differential responses of immature and mature neuron populations were also observed, alongside abnormal hippocampal neurogenesis. Our scRNAseq library provides a new layer of knowledge on single cell gene expression in prion disease, and is a basis for a more detailed understanding of cellular interplay that leads to neurodegeneration.

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“…3a) to maximize production of inflammatory modulators. MSCs change phenotype of microglia from the activated and inflammatory M1 phenotype to the neuroprotective M2 phenotype 33,54,55 www.nature.com/scientificreports/ increased M1 markers 23,25,39 , although the role of M1 and M2 microglia has only begun to be elucidated in prion pathogenesis 23,47,56 .…”

Section: Discussionmentioning

confidence: 99%

Adipose-derived mesenchymal stromal cells decrease prion-induced glial inflammation in vitro

Hay

Murphy

Popichak

et al. 2022

Sci Rep

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Prion diseases are characterized by the cellular prion protein, PrPC, misfolding and aggregating into the infectious prion protein, PrPSc, which leads to neurodegeneration and death. An early sign of disease is inflammation in the brain and the shift of resting glial cells to reactive astrocytes and activated microglia. Few therapeutics target this stage of disease. Mesenchymal stromal cells produce anti-inflammatory molecules when exposed to inflammatory signals and damaged tissue. Here, we show that adipose-derived mesenchymal stromal cells (AdMSCs) migrate toward prion-infected brain homogenate and produce the anti-inflammatory molecules transforming growth factor β (TGFβ) and tumor necrosis factor-stimulated gene 6 (TSG-6). In an in vitro model of prion exposure of both primary mixed glia and BV2 microglial cell line, co-culturing with AdMSCs led to a significant decrease in inflammatory cytokine mRNA and markers of reactive astrocytes and activated microglia. This protection against in vitro prion-associated inflammatory responses is independent of PrPSc replication. These data support a role for AdMSCs as a beneficial therapeutic for decreasing the early onset of glial inflammation and reprogramming glial cells to a protective phenotype.

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The role of microglia in prion diseases and possible therapeutic targets: a literature review

Cited by 10 publications

References 67 publications

Electroacupuncture relieves chronic pain by promoting microglia M2 polarization in lumbar disc herniation rats

Electroacupuncture relieves chronic pain by promoting microglia M2 polarization in lumbar disc herniation rats

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

Adipose-derived mesenchymal stromal cells decrease prion-induced glial inflammation in vitro

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