Microglia depletion increase brain injury after acute ischemic stroke in aged mice

Lee, Shirley Marino; Hudobenko, Jacob; McCullough, Louise D.; Chauhan, Anjali

doi:10.1016/j.expneurol.2020.113530

Cited by 47 publications

(32 citation statements)

References 10 publications

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“…Conditional deletion of CSF1R, inducible diphtheria toxin models, and CSF1R antagonists provide alternative approaches. However, these models induce the rapid death of adult microglia leading to pleotropic effects on astrocytes and promoting T cell recruitment to the brain (Elmore et al, 2014;Marino Lee et al, 2021;Unger et al, 2018). In addition, surviving microglia quickly proliferate to repopulate the microglial niche so that the long-term consequences of microglia absence with such models cannot be effectively studied (Bruttger et al, 2015;Han et al, 2020;Lund et al, 2018;Pons et al, 2020Pons et al, , 2021.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, FIRE mice do not exhibit hydrocephalus and other neurological impacts or the severe peripheral growth and developmental abnormalities reported in constitutive Csf1r À/À rodents and humans (Hume et al, 2020;Patkar et al, 2021;Rojo et al, 2019). This model of microglial deficiency also avoids the confounding impacts of CSF1R antagonists, which drive widespread microglial apoptosis, leading to pleiotropic effects on astrocyte function and T cell recruitment (Elmore et al, 2014;Marino Lee et al, 2021;Unger et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

et al. 2022

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“…In fact, microglia have been implicated in the exacerbation of damage following glutamate excitotoxicity and ischemic stroke, due to increased production of ROS and pro-inflammatory mediators ( Ma et al, 2017 ; Qin et al, 2019 ; Lian et al, 2020 ). At the same time, microglia also play an important protective role following tissue stroke damage, so the duality of their contribution to physiology/pathophysiology cannot be over-simplified to just a negative contribution to damage ( Ma et al, 2017 ; Qin et al, 2019 ; Marino Lee et al, 2021 ). The age-related loss of circulating IGF-1 is associated with increased microglial activation, neuroinflammation, and susceptibility to a compromised blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

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Ashmore

Vijayasankar

et al. 2021

Front. Aging Neurosci.

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The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

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“…However, as microglia may be pathologically activated at baseline in the aged brain, we tested if depletion could lead to beneficial effects in aged models. Aged animals (18–19 months), depleted of microglia fed (PLX5622) for 3 weeks before an induced stroke, also had increased infarct damage and myeloid cell infiltration at 24 and 72 h after stroke [ 153 ]. Despite the dysregulated state of aged microglia, this experiment suggests that aged microglia have some beneficial effects during the acute phase of ischemic stroke.…”

Section: Age-related Changes In Stroke-induced Inflammationmentioning

confidence: 99%

Age-related immune alterations and cerebrovascular inflammation

et al. 2021

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Aging is associated with chronic systemic inflammation, which contributes to the development of many age-related diseases, including vascular disease. The world’s population is aging, leading to an increasing prevalence of both stroke and vascular dementia. The inflammatory response to ischemic stroke is critical to both stroke pathophysiology and recovery. Age is a predictor of poor outcomes after stroke. The immune response to stroke is altered in aged individuals, which contributes to the disparate outcomes between young and aged patients. In this review, we describe the current knowledge of the effects of aging on the immune system and the cerebral vasculature and how these changes alter the immune response to stroke and vascular dementia in animal and human studies. Potential implications of these age-related immune alterations on chronic inflammation in vascular disease outcome are highlighted.

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Microglia depletion increase brain injury after acute ischemic stroke in aged mice

Cited by 47 publications

References 10 publications

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

Age-related immune alterations and cerebrovascular inflammation

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