Neurotoxic reactive astrocytes induce cell death via saturated lipids

Guttenplan, Kevin A.; Weigel, Maya K.; Prakash, Priya; Wijewardhane, Prageeth R.; Hasel, Philip; Rufen-Blanchette, Uriel; Münch, Alexandra E.; Blum, Jacob A.; Fine, Jonathan; Neal, Mikaela C.; Bruce, Kimberley D.; Gitler, Aaron D.; Chopra, Gaurav; Liddelow, Shane A.; Barres, Ben A.

doi:10.1038/s41586-021-03960-y

Cited by 390 publications

(344 citation statements)

References 38 publications

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“…In demyelinating diseases, astrocytes respond quickly by upregulating several proinflammatory cytokines, chemokines, as well as remyelination-signaling molecules ( Williams et al, 2007 ). A recent study revealed that reactive astrocytes could be induced by inflammatory microglia cells and cause the death of neurons and OLs through producing saturated lipids ( Liddelow et al, 2017 ; Guttenplan et al, 2021 ). In addition, astrocytes may also play a role in recruiting phagocytic microglia in areas of demyelination ( Skripuletz et al, 2013 ).…”

Section: Mechanisms Of Inhibited Myelinogenesis During Agingmentioning

confidence: 99%

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

Huang

Xiao

et al. 2021

Front. Aging Neurosci.

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Aging affects almost all the aspects of brain functions, but the mechanisms remain largely undefined. Increasing number of literatures have manifested the important role of glial cells in regulating the aging process. Oligodendroglial lineage cell is a major type of glia in central nervous system (CNS), composed of mature oligodendrocytes (OLs), and oligodendroglia precursor cells (OPCs). OLs produce myelin sheaths that insulate axons and provide metabolic support to meet the energy demand. OPCs maintain the population throughout lifetime with the abilities to proliferate and differentiate into OLs. Increasing evidence has shown that oligodendroglial cells display active dynamics in adult and aging CNS, which is extensively involved in age-related brain function decline in the elderly. In this review, we summarized present knowledge about dynamic changes of oligodendroglial lineage cells during normal aging and discussed their potential roles in age-related functional decline. Especially, focused on declined myelinogenesis during aging and underlying mechanisms. Clarifying those oligodendroglial changes and their effects on neurofunctional decline may provide new insights in understanding aging associated brain function declines.

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Section: Mechanisms Of Inhibited Myelinogenesis During Agingmentioning

confidence: 99%

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

Huang

Xiao

et al. 2021

Front. Aging Neurosci.

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“…These pathogenic reactive astrocytes are found in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral 2 sclerosis, vanishing white matter disease 10 , and multiple sclerosis 1,11 . Thus, there is considerable interest in modulating pathological reactive astrocytes to reduce the progression of these diseases 3,6,12 . Here, we develop an astrocyte discovery platform and leverage the power of highthroughput phenotypic drug screening 13 to identify modulators of reactive astrocytes.…”

Section: Mainmentioning

confidence: 99%

“…3g). These included RelA/p65 direct target MHC Class I genes involved in the antigen presentation function blocked by RGFP966, and non-RelA/p65 direct target genes associated with the metabolism and transport of very-long chain fatty acids that were recently shown to partially mediate pathological reactive astrocyte toxicity to neurons and oligodendrocytes 6 (Fig. 3h-j).…”

Section: Hdac3 Inhibition Mediates a Switch Between Pro-and Anti-inflammatory Astrocyte Programsmentioning

confidence: 99%

“…Astrocytes in the central nervous system (CNS) play important homeostatic roles that include trophic support of neurons, promotion of functional synapse formation, and formation and maintenance of the blood-brain barrier [7][8][9] . In the context of disease, injury, or normal aging, astrocytes become reactive and can adopt a pathological state that kills neurons and oligodendrocytes 6 . These pathogenic reactive astrocytes are found in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral 2 sclerosis, vanishing white matter disease 10 , and multiple sclerosis 1,11 .…”

Section: Mainmentioning

confidence: 99%

“…In neurodegenerative diseases, inflammatory reactive astrocytes are abundant and contribute to progressive cell loss. Modulating the state or function of these reactive astrocytes thereby represents an attractive therapeutic goal 5,6 . Leveraging a cellular phenotypic screening platform, we show that chemical inhibitors of HDAC3 effectively block pathological astrocyte reactivity.…”

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Chemical inhibition of pathological reactive astrocytes promotes neural protection

Clayton

Kristell

Allan

et al. 2021

Preprint

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Disease, injury, and aging induce reactive astrocyte states with pathological functions1-4. In neurodegenerative diseases, inflammatory reactive astrocytes are abundant and contribute to progressive cell loss. Modulating the state or function of these reactive astrocytes thereby represents an attractive therapeutic goal5,6. Leveraging a cellular phenotypic screening platform, we show that chemical inhibitors of HDAC3 effectively block pathological astrocyte reactivity. Inhibition of HDAC3 reduces molecular and functional features of reactive astrocytes in vitro including inflammatory gene expression, cytokine secretion, and antigen presentation. Transcriptional and chromatin mapping studies show that HDAC3 inhibition mediates a switch between pro-inflammatory and anti-inflammatory states, which disarms the pathological functions of reactive astrocytes. Systemic administration of a blood-brain barrier penetrant chemical inhibitor of HDAC3, RGFP966, blocks reactive astrocyte formation and promotes axonal protection in vivo. Collectively, these results establish a platform for discovering chemical modulators of reactive astrocyte states, inform the mechanisms controlling astrocyte reactivity, and demonstrate the therapeutic potential of modulating astrocyte reactivity for neurodegenerative diseases.

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Neuron–Glial Interactions in Health and Brain Cancer

Pan

Monje

2022

Advanced Biology

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Brain tumors are devastating diseases of the central nervous system. Brain tumor pathogenesis depends on both tumor‐intrinsic oncogenic programs and extrinsic microenvironmental factors, including neurons and glial cells. Glial cells (oligodendrocytes, astrocytes, and microglia) make up half of the cells in the brain, and interact with neurons to modulate neurodevelopment and plasticity. Many brain tumor cells exhibit transcriptomic profiles similar to macroglial cells (oligodendrocytes and astrocytes) and their progenitors, making them likely to subvert existing neuron–glial interactions to support tumor pathogenesis. For example, oligodendrocyte precursor cells, a putative glioma cell of origin, can form bona fide synapses with neurons. Such synapses are recently identified in gliomas and drive glioma pathophysiology, underscoring how brain tumor cells can take advantage of neuron–glial interactions to support cancer progression. In this review, it is briefly summarized how neurons and their activity normally interact with glial cells and glial progenitors, and it is discussed how brain tumor cells utilize neuron–glial interactions to support tumor initiation and progression. Unresolved questions on these topics and potential avenues to therapeutically target neuron–glia–cancer interactions in the brain are also pointed out.

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Neurotoxic reactive astrocytes induce cell death via saturated lipids

Cited by 390 publications

References 38 publications

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

Chemical inhibition of pathological reactive astrocytes promotes neural protection

Neuron–Glial Interactions in Health and Brain Cancer

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