Signaling pathways regulating neuron–glia interaction and their implications in Alzheimer's disease

Lian, Hong; Zheng, Hui

doi:10.1111/jnc.13424

Cited by 65 publications

(51 citation statements)

References 296 publications

(230 reference statements)

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“…Besides complement-mediated synapse removal, other pathways have been described to be involved in glia-neuron interaction that might also result in synapse elimination (reviewed in [ 118 ]). Astrocytes have been described to be implicated in activity-dependent synapse elimination via multiple EGF-like domains 10 (MEGF10) and Mer tyrosine kinase (MERTK) pathways [ 119 ].…”

Section: Other Pathways Involved In Synapse Removalmentioning

confidence: 99%

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Luchena

Zuazo-Ibarra

Alberdi

et al. 2018

Mediators of Inflammation

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Synapse loss is an early manifestation of pathology in Alzheimer's disease (AD) and is currently the best correlate to cognitive decline. Microglial cells are involved in synapse pruning during development via the complement pathway. Moreover, recent evidence points towards a key role played by glial cells in synapse loss during AD. However, further contribution of glial cells and the role of neurons to synapse pathology in AD remain not well understood. This review is aimed at comprehensively reporting the source and/or cellular localization in the CNS—in microglia, astrocytes, or neurons—of the triggering components (C1q, C3) of the classical complement pathway involved in synapse pruning in development, adulthood, and AD.

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Section: Other Pathways Involved In Synapse Removalmentioning

confidence: 99%

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Luchena

Zuazo-Ibarra

Alberdi

et al. 2018

Mediators of Inflammation

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“…Prolonged activation of glial cells, microglia and astrocytes in particular, and the release of proinflammatory cytokines, chemokines, and reactive oxygen and nitrogen species, create a neurotoxic environment which could exacerbate the progression of AD (9)(10)(11). Recent genome wide association studies have identified multiple immune related gene variants as risk factors for late-onset AD, supporting a major contributing role of innate immunity and neuroinflammation in AD (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

Ghosh

Comerota

Wan

et al. 2020

Preprint

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AbstractNeuroinflammation has been increasingly recognized to play critical roles in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH). We found that sEH is predominantly expressed in astrocytes where its levels are significantly elevated in postmortem human AD brains and in β-amyloid mouse models, and the latter is correlated with drastic reductions of brain EpFA levels. Using a highly potent and specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report here that TPPU treatment potently protected against LPS-induced inflammation in vitro and in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation, and this is associated with reduced β–amyloid pathology and improved synaptic integrity and cognitive function. Importantly, TPPU treatment reinstated and positively correlated EpFA levels in the 5xFAD mouse brain, demonstrating its brain penetration and target engagement. These findings support TPPU as a novel therapeutic target for the treatment of AD and related disorders.One Sentence SummaryWe show that soluble epoxide hydrolase is upregulated in AD patients and mouse models, and that inhibition of this lipid metabolic pathway using an orally bioavailable small molecule inhibitor is effective in restoring brain epoxy fatty acids, ameliorating AD neuropathology and improving synaptic and cognitive function.

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“…Intracellular Ca 2+ concentration ([Ca 2+ ] i ) changes are an important signal for a wide spectrum of cell activities from short-term neurotransmitter release to long-term control of gene expression ( Berridge, 2014 , Lian and Zheng, 2016 , Mintz et al., 1995 , Simms and Zamponi, 2014 , Soderling and Derkach, 2000 , Yagami et al., 2012 ). The voltage-gated Ca 2+ channels (Ca V s) at the plasma membrane are encoded by various isoforms in different cells and are the main pathway for Ca 2+ influx.…”

Section: Introductionmentioning

confidence: 99%

Calmodulin modulates the Ca 2+ -dependent inactivation and expression level of bovine Ca V 2.2 expressed in HEK293T cells

2017

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Ca2+ influx through voltage-gated Ca2+ channels (CaVs) at the plasma membrane is the major pathway responsible for the elevation of the intracellular Ca2+ concentration ([Ca2+]i), which activates various physiological activities. Calmodulin (CaM) is known to be involved in the Ca2+-dependent inactivation (CDI) of several types of CaVs; however, little is known about how CaM modulates CaV2.2. Here, we expressed CaV2.2 with CaM or CaM mutants with a Ca2+-binding deficiency in HEK293T cells and measured the currents to characterize the CDI. The results showed that CaV2.2 displayed a fast inactivation with Ca2+ but not Ba2+ as the charge carrier; when CaV2.2 was co-expressed with CaM mutants with a Ca2+-binding deficiency, the level of inactivation decreased. Using glutathione S-transferase-tagged CaM or CaM mutants as the bait, we found that CaM could interact with the intracellular C-terminal fragment of CaV2.2 in the presence or absence of Ca2+. However, CaM and its mutants could not interact with this fragment when mutations were generated in the conserved amino acid residues of the CaM-binding site. CaV2.2 with mutations in the CaM-binding site showed a greatly reduced current that could be rescued by CaM12 (Ca2+-binding deficiency at the N-lobe) overexpression; in addition, CaM12 enhanced the total expression level of CaV2.2, but the ratio of CaV2.2 present in the membrane to the total fraction remained unchanged. Together, our data suggest that CaM, with different Ca2+-binding abilities, modulates not only the inactivation of CaV2.2 but also its expression to regulate Ca2+-related physiological activities.

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Signaling pathways regulating neuron–glia interaction and their implications in Alzheimer's disease

Cited by 65 publications

References 296 publications

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

Calmodulin modulates the Ca 2+ -dependent inactivation and expression level of bovine Ca V 2.2 expressed in HEK293T cells

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