Microglial WNT5A supports dendritic spines maturation and neuronal firing

Yeh, Hana; Woodbury, Maya E.; Ingraham-Dixie, Katie; Ikezu, Tsuneya; Ikezu, Seiko

doi:10.1016/j.bbi.2022.11.003

Cited by 10 publications

(7 citation statements)

References 74 publications

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“…For instance, Wnt5a expression in microglia activates the non-canonical Wnt signaling pathway, which initiates an immune response against nerve injury by increasing the genetic expression of TNF-α, IL-6, and IL-1β. 209 Microglia in different activation states secrete distinct Wnt proteins; for example, M1 phenotype microglia secrete Wnt5a, whereas M2 phenotype microglia secrete Wnt7a. 210 The Wnt signaling pathway has been implicated in the regulation of the neuro-inflammation caused by cerebral I/R injury.…”

Section: Wnt Pathways and Organ I/r Injurymentioning

confidence: 99%

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Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

Zhang,

Liu,

Meng

et al. 2024

Sig Transduct Target Ther

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Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca2+-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.

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Section: Wnt Pathways and Organ I/r Injurymentioning

confidence: 99%

“…One possibility is that Wnt5a drives the non-canonical Wnt signaling pathway and induces inflammation by promoting microglial polarization toward the M1 phenotype. 209 , 210 …”

Section: Wnt Pathways and Organ I/r Injurymentioning

confidence: 99%

Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

Zhang,

Liu,

Meng

et al. 2024

Sig Transduct Target Ther

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“…Wnt5a is a critical signaling molecule in physiological and pathological conditions, including embryonic development, tumors, inflammatory diseases, and neurodegeneration [53][54][55]. Previous research found that Wnt5a expression is responsible for sustained inflammation and macrophage activation through autocrine and paracrine signaling [56].…”

Section: Mir-26a-5p@a-msn-mg1 Delivery System Maintains a Prolonged R...mentioning

confidence: 99%

A novel microglia-targeting strategy based on nanoparticle-mediated delivery of miR-26a-5p for long-lasting analgesia in chronic pain

Lu,

Liu,

Wang

et al. 2024

J Nanobiotechnol

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Accumulating evidence supports the notion that microglia play versatile roles in different chronic pain conditions. However, therapeutic strategies of chronic pain by targeting microglia remain largely overlooked. This study seeks to develop a miRNA-loaded nano-delivery system by targeting microglia, which could provide a decent and long-lasting analgesia for chronic pain. Surface aminated mesoporous silica nanoparticles were adopted to load miR-26a-5p, a potent analgesic miRNA, by electrostatic adsorption, which can avoid miR-26a-5p is rapidly released and degraded. Then, targeting peptide MG1 was modified on the surface of aminated mesoporous silica particles for microglia targeting. In peripheral nerve injury induced neuropathic pain model, a satisfactory anti-allodynia effect with about 6 weeks pain-relief duration were achieved through targeting microglia strategy, which decreased microglia activation and inflammation by Wnt5a, a non-canonical Wnt pathway. In inflammatory pain and chemotherapy induced peripheral neuropathic pain, microglia targeting strategy also exhibited more efficient analgesia and longer pain-relief duration than others. Overall, we developed a microglia-targeting nano-delivery system, which facilitates precisely miR-26a-5p delivery to enhance analgesic effect and duration for several chronic pain conditions. Graphical Abstract

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“…Secretory factors derived from microglia conditioned medium have been shown to promote neuronal survival and maturation 83,84 by regulating synaptic responses, density, and network connectivity in primary neurons cultured in such microglia conditioned medium [85][86][87] . To determine whether media from MAPT IVS10+16 iMGL is sufficient to alter healthy neurons, we cultured iPSC-derived neurons driven by dox-inducible Ngn2, which allowed us to generate a homogenous population of excitatory, glutamatergic neurons.…”

Section: Mapt Ivs10+16 Imgl Secretome Alters Neuronal Synapsesmentioning

confidence: 99%

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia

Iyer,

Vermunt,

Mirfakhar

et al. 2024

Preprint

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Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring the MAPT IVS10+16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered that MAPT IVS10+16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors from MAPT IVS10+16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observed in vitro were recapitulated in human brain tissue and cerebrospinal fluid from MAPT mutations carriers. Together, our findings that MAPT IVS10+16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutic strategies.

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Microglial WNT5A supports dendritic spines maturation and neuronal firing

Cited by 10 publications

References 74 publications

Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

A novel microglia-targeting strategy based on nanoparticle-mediated delivery of miR-26a-5p for long-lasting analgesia in chronic pain

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia

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