Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer's disease mice via the downregulation of TLR4/Myd88/NF-κB pathway

Guo, Minfang; Zhang, Huiyu; Li, Yanhua; Gu, Qingfang; Wei, Wenyue; Wang, Yuyin; Zhang, Xiaojuan; Liu, Xiaoqin; Song, Lijuan; Chai, Zhi; Yu, Jiezhong; Ma, Cun‐Gen

doi:10.1016/j.jneuroim.2020.577284

Cited by 50 publications

(29 citation statements)

References 43 publications

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“…Because microglia-derived cytokines were reported to drive astrocyte conversion into the neurotoxic A1 phenotype, it was initially hypothesized that blocking this process could be a beneficial therapeutic approach to halt neurodegeneration. In keeping with this, the administration of compounds blocking microglia's ability to elicit A1 astrocytes ameliorated the phenotype, prevented neuron loss, and prolonged survival in mouse models of PD [106] and AD [107]. Furthermore, the concomitant genetic ablation of IL-1α, TNFα, and C1q prevented the emergence of A1 astrocytes and extended survival in a mouse model of ALS [108].…”

Section: Modulating Astrocyte Function By Tuning the Incoming Signalingmentioning

confidence: 63%

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Valori

Possenti

Brambilla

et al. 2021

Cells

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Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems.

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Section: Modulating Astrocyte Function By Tuning the Incoming Signalingmentioning

confidence: 63%

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Valori

Possenti

Brambilla

et al. 2021

Cells

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“…Furthermore, ROCK inhibition circumvented the stunted growth associated with IGF-1 inhibition, suggesting a possible route of rescue in our mutant mice. This was particularly interesting considering previous studies have shown small molecule inhibitors of ROCK, including HF, can rescue spatial learning and memory in aged mice and rodent models of neurodegeneration (Guo et al, 2020; Huentelman et al, 2009; Yu et al, 2017). Unfortunately, we did not observe a rescue of synapse number or learning and memory despite our doses of HF falling within the range of these previous studies.…”

Section: Discussionmentioning

confidence: 96%

“…Expression and activity of the RhoA/ROCK pathway are upregulated in advanced age and are further upregulated in cognitively-impaired aged animals (VanGuilder Starkey et al, 2013). In aged rats and mouse models of Alzheimer’s Disease and intellectual disability, ROCK inhibition rescues spatial learning and memory impairments (Busti et al, 2020; Guo et al, 2020; Huentelman et al, 2009; Meziane et al, 2016; Yu et al, 2017). If IGF-1 regulates ROCK activity, then the age-related loss of IGF-1 could account for the upregulation of this growth-limiting pathway.…”

Section: Introductionmentioning

confidence: 99%

Adulthood Deficiency of the Insulin-like Growth Factor-1 Receptor in Hippocampal Neurons Impairs Cell Structure and Spatial Learning and Memory in Male and Not Female Mice

Hayes

Hodges

Marshall

et al. 2021

Preprint

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Reductions in insulin-like growth factor-1 (IGF-1) are associated with cognitive impairment and increased risk of neurodegenerative disease in advanced age. In mouse models, reduced IGF-1 early-in-life leads to memory impairments and synaptic dysfunction; however, these models are limited by systemic reductions in IGF-1. We hypothesized that IGF-1 continues to promote hippocampal neuron structure and function after development, and as such, the loss of IGF-1 signaling in adult neurons would lead to impaired spatial learning and memory. To test this, the IGF-1 receptor (IGF-1R) was genetically targeted in hippocampal neurons of adult male and female mice. Male mice deficient in neuronal IGF-1R exhibited spatial learning impairments as evidenced by increased pathlength and errors in the radial arm water maze. No differences in learning and memory were observed in female mice. Golgi-Cox staining revealed a reduced number of dendritic boutons of neurons the CA1 region of the hippocampus in male mice. Decreased MAPK and increased ROCK activity were also observed in these tissues. In vitro studies revealed that impaired neurite outgrowth due to inhibited IGF-1R signaling could be rescued by pharmacological inhibitors of ROCK. However, ROCK inhibition in neuronal IGF-1R deficient mice did not fully rescue learning impairments or bouton numbers. Together, our study highlights that IGF-1 continues to support spatial learning and memory and neuronal structure in adulthood.

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“…Meisoindigo promotes M1-to-M2 microglial phenotype transition by inhibiting the TLR4/NF-κB signaling pathway, which effectively prevents focal cerebral ischemia-reperfusion injury ( Ye et al, 2019 ). Fasudil inhibits the expression of TLR4, MyD88, and NF-κB; moreover, it promotes microglia transition to the M2 phenotype in AD mice through the TLR4/MyD88/NF-κB pathway ( Guo et al, 2020 ). Contrastingly, activating the TLR4/NF-κB signaling pathway promotes microglial M1 polarization and aggravates nerve injury ( Chen et al, 2019 ).…”

Section: Signal Pathways Involved In Regulating Microglial Phenotypic Transitionmentioning

confidence: 99%

Microglial Phenotypic Transition: Signaling Pathways and Influencing Modulators Involved in Regulation in Central Nervous System Diseases

Shui

Sun

et al. 2021

Front. Cell. Neurosci.

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Microglia are macrophages that reside in the central nervous system (CNS) and belong to the innate immune system. Moreover, they are crucially involved in CNS development, maturation, and aging; further, they are closely associated with neurons. In normal conditions, microglia remain in a static state. Upon trauma or lesion occurrence, microglia can be activated and subsequently polarized into the pro-inflammatory or anti-inflammatory phenotype. The phenotypic transition is regulated by numerous modulators. This review focus on the literature regarding the modulators and signaling pathways involved in regulating the microglial phenotypic transition, which are rarely mentioned in other reviews. Hence, this review provides molecular insights into the microglial phenotypic transition, which could be a potential therapeutic target for neuroinflammation.

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Fasudil inhibits the activation of microglia and astrocytes of transgenic Alzheimer's disease mice via the downregulation of TLR4/Myd88/NF-κB pathway

Cited by 50 publications

References 43 publications

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Adulthood Deficiency of the Insulin-like Growth Factor-1 Receptor in Hippocampal Neurons Impairs Cell Structure and Spatial Learning and Memory in Male and Not Female Mice

Microglial Phenotypic Transition: Signaling Pathways and Influencing Modulators Involved in Regulation in Central Nervous System Diseases

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