She Doesn’t Even Go Here: The Role of Inflammatory Astrocytes in CNS Disorders

Reid, Jacqueline Kelsey; Kuipers, Hedwich F.

doi:10.3389/fncel.2021.704884

Cited by 27 publications

(18 citation statements)

References 118 publications

(187 reference statements)

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“…The Cxcl2 gene codes for chemokine (C-X-C motif) ligand 2, also known as macrophage inflammatory protein two, a proinflammatory chemokine produced and released by astrocytes mediating neuroinflammatory responses [ 62 , 63 ]. Gbp2 is a known marker for A1 neuroinflammatory/neurotoxic astrocytes [ 64 , 65 ]. Meanwhile, C3 , Cfb , and Serping1 , all markers of A1 reactive astrocytes [ 66 , 67 ], were all commonly up-regulated in both Aβ42 and Aβ40 fibril-treated astrocytes.…”

Section: Resultsmentioning

confidence: 99%

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

et al. 2022

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Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of PAI-1, MMP9, MMP12, CCL2, and C1r in plaque-associated microglia, and iNOS, GBP2, and C3D in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including IL1β and TNFα in astrocytes, and microglial activation and TGFβ1 in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment.

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Section: Resultsmentioning

confidence: 99%

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

et al. 2022

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“…Categorically astrocytes have been classified as having the proinflammatory-A1 phenotype and neuroprotective-A2 phenotype similar to the M1/M2 classification of microglia [104]. However, the reactive states of astrocytes have been found to go beyond these two categories thereby making the scientific community abandon this binary gross division [104,105]. However, astrocytes do acquire an inflammatory subtype with specialized markers that has significant relevance in pathological states.…”

Section: Tgf-β and Astrocytesmentioning

confidence: 99%

TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized Tau perspective

Kapoor

Chinnathambi

2023

J Neuroinflammation

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Microtubule-associated protein, Tau has been implicated in Alzheimer's disease for its detachment from microtubules and formation of insoluble intracellular aggregates within the neurons. Recent findings have suggested the expulsion of Tau seeds in the extracellular domain and their prion-like propagation between neurons. Transforming Growth Factor-β1 (TGF-β1) is a ubiquitously occurring cytokine reported to carry out immunomodulation and neuroprotection in the brain. TGF-β-mediated regulation occurs at the level of neuronal survival and differentiation, glial activation (astrocyte and microglia), amyloid production–distribution–clearance and neurofibrillary tangle formation, all of which contributes to Alzheimer's pathophysiology. Its role in the reorganization of cytoskeletal architecture and remodelling of extracellular matrix to facilitate cellular migration has been well-documented. Microglia are the resident immune sentinels of the brain responsible for surveying the local microenvironment, migrating towards the beacon of pertinent damage and phagocytosing the cellular debris or patho-protein deposits at the site of insult. Channelizing microglia to target extracellular Tau could be a good strategy to combat the prion-like transmission and seeding problem in Alzheimer's disease. The current review focuses on reaffirming the role of TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization and considers utilizing the approach of TGF-β-triggered microglia-mediated targeting of extracellular patho-protein, Tau, as a possible potential strategy to combat Alzheimer's disease.

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“…Transcript analyses revealed markers common to all reactive astrocytes (e.g., GFAP [ 178 , 302 ]). The expression of complement protein C3 is a marker for inflammatory “A1” astrocytes [ 178 , 208 , 284 , 303 , 304 ]. Complement proteins were found to be highly elevated in the brain of MS patients, particularly in cortical grey matter lesions [ 305 , 306 , 307 , 308 ].…”

Section: Primer On Astrocytes: a Network Of Guardians Of Brain Homeos...mentioning

confidence: 99%

Synapse Dysfunctions in Multiple Sclerosis

Schwarz

Schmitz

2023

IJMS

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Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) affecting nearly three million humans worldwide. In MS, cells of an auto-reactive immune system invade the brain and cause neuroinflammation. Neuroinflammation triggers a complex, multi-faceted harmful process not only in the white matter but also in the grey matter of the brain. In the grey matter, neuroinflammation causes synapse dysfunctions. Synapse dysfunctions in MS occur early and independent from white matter demyelination and are likely correlates of cognitive and mental symptoms in MS. Disturbed synapse/glia interactions and elevated neuroinflammatory signals play a central role. Glutamatergic excitotoxic synapse damage emerges as a major mechanism. We review synapse/glia communication under normal conditions and summarize how this communication becomes malfunctional during neuroinflammation in MS. We discuss mechanisms of how disturbed glia/synapse communication can lead to synapse dysfunctions, signaling dysbalance, and neurodegeneration in MS.

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She Doesn’t Even Go Here: The Role of Inflammatory Astrocytes in CNS Disorders

Cited by 27 publications

References 118 publications

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized Tau perspective

Synapse Dysfunctions in Multiple Sclerosis

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