Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery

Jiang, Lu; Mu, Hongfeng; Xu, Fei; Xie, Di; Su, Wei; Xu, Jing; Sun, Zeyu; Liu, Silvia; Luo, Jianhua; Shi, Yejie; Leak, Rehana K.; Wechsler, Lawrence R.; Chen, Jun; Hu, Xiaoming

doi:10.1177/0271678x20902542

Cited by 38 publications

(32 citation statements)

References 69 publications

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“…Changes of the immune response with a shift towards a proinflammatory state and alterations of microglial differentiation and function are thought to play a key role for the reduced regenerative capacity of older brains. 115 – 117 There is even evidence for changes in the gut microbiota of aged mice followed by increased levels of systemic proinflammatory cytokines resulting in worse outcome after stroke. 118 Not so surprisingly, there is proof that not only the endogenous regenerative capacity of the aged brain is reduced but also the response to various treatments when compared to younger animals.…”

Section: Specific Requirements and Pitfalls In Recovery Studiesmentioning

confidence: 99%

Principles and requirements for stroke recovery science

Sommer

Schäbitz

2020

J Cereb Blood Flow Metab

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The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behavioral level occurring after brain ischemia eventually ending up with any measurable improvement of various clinical parameters. A detailed knowledge of the spontaneously occurring post-ischemic regeneration processes is the indispensable prerequisite for any therapeutic approaches aiming to modify these responses to enhance post-stroke recovery. This review will briefly illuminate the molecular mechanisms of post-ischemic regeneration and the principle possibilities to foster post-stroke recovery. In this context, recent translational approaches are analyzed. Finally, the principal and specific requirements and pitfalls in stroke recovery research as well as potential explanations for translational failures will be discussed.

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Section: Specific Requirements and Pitfalls In Recovery Studiesmentioning

confidence: 99%

Principles and requirements for stroke recovery science

Sommer

Schäbitz

2020

J Cereb Blood Flow Metab

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“…However, under pathological conditions, the effect of microglial phagocytosis is considered to be paradoxical 4 . On one hand, microglia phagocytosis may prevent secondary apoptosis‐induced inflammation by releasing anti‐inflammatory cytokines and by inhibiting pro‐inflammatory cytokines 5 . On the other hand, microglial phagocytosis appears to activate respiratory burst, resulting in the release of neurotoxic reactive oxygen species (ROS) 4 .…”

Section: Introduction and Classification Of Pathological Microglial Pmentioning

confidence: 99%

Central nervous system diseases related to pathological microglial phagocytosis

et al. 2021

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Microglia are important phagocytes of the central nervous system (CNS). They play an important role in protecting the CNS by clearing necrotic tissue and apoptotic cells in many CNS diseases. However, recent studies have found that microglia can phagocytose parts of neurons excessively, such as the neuronal cell body, synapse, or myelin sheaths, before or after the onset of CNS diseases, leading to aggravated injury and impaired tissue repair. Meanwhile, reduced phagocytosis of synapses and myelin results in abnormal circuit connections and inhibition of remyelination, respectively. Previous studies focused primarily on the positive effects of microglia phagocytosis, whereas only a few studies have focused on the negative effects. In this review, we use the term "pathological microglial phagocytosis" to refer to excessive or reduced phagocytosis by microglia that leads to structural or functional abnormalities in target cells and brain tissue. The classification of pathological microglial phagocytosis, the composition, and activation of related signaling pathways, as well as the process of pathological phagocytosis in various kinds of CNS diseases, are described in this review. We hypothesize that pathological microglial phagocytosis leads to aggravation of tissue damage and negative functional outcome. For example, excessive microglial phagocytosis of synapses can be observed in Alzheimer's disease and schizophrenia, leading to significant synapse loss and memory impairment. In Parkinson's disease, ischemic stroke, and traumatic brain injury, excessive microglial phagocytosis of neuronal cell bodies causes impaired gray matter recovery and sensory dysfunction. We therefore believe that more studies should focus on the mechanism of pathological microglial phagocytosis and activation to uncover potential targets of therapeutic intervention.

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“…As resident microglia serve pro‐angiogenic effects in the brain (Brandenburg et al, 2016; Jiang et al, 2020; Mastorakos et al, 2021), we co‐stained Iba‐1 and isolectin B4 on brain sections of 9‐month‐old APP tg Myd88 fl/wt Cre +/− and APP tg Myd88 fl/wt Cre −/− mice and counted microglia with and without contact with blood vessels in CA1 area of the hippocampus (Figure 5f). We observed that haploinsufficiency of MyD88 significantly increased the distribution of microglia to blood vessels (Figure 5g; one‐way ANOVA followed by post‐hoc test, p <.05).…”

Section: Resultsmentioning

confidence: 99%

Haploinsufficiency of microglial MyD88 ameliorates Alzheimer's pathology and vascular disorders in APP/PS1‐transgenic mice

Quan

Luo

Hao

et al. 2021

Glia

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Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD); however, their effects on amyloid pathology and neurodegeneration remain inconclusive. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1‐transgenic mice by 6 months and analyzed AD‐associated pathologies by 9 months. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid β (Aβ) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf‐α and il‐1β, in both brain tissues and individual microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aβ deposits, which might facilitate Aβ clearance. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1‐transgenic mice, which was associated with up‐regulated transcription of osteopontin and insulin‐like growth factor genes in microglia. Moreover, MyD88‐haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1‐transgenic mice. Cell culture experiments further showed that treatments with interleukin‐1β decreased LRP1 expression in pericytes. In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro‐inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1‐mediated Aβ clearance in the brain of APP/PS1‐transgenic mice, all of which improves neuronal function of AD mice.

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Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery

Cited by 38 publications

References 69 publications

Principles and requirements for stroke recovery science

Principles and requirements for stroke recovery science

Central nervous system diseases related to pathological microglial phagocytosis

Haploinsufficiency of microglial MyD88 ameliorates Alzheimer's pathology and vascular disorders in APP/PS1‐transgenic mice

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