Microglial <scp>CX3CR1</scp> production increases in Alzheimer's disease and is regulated by noradrenaline

González‐Prieto, Marta; Gutiérrez, Irene L.; García‐Bueno, Borja; Caso, Javier R.; Leza, Juan C.; Ortega‐Hernández, Adriana; Gómez‐Garre, Dulcenombre; Madrigal, José L. M.

doi:10.1002/glia.23885

Cited by 22 publications

(14 citation statements)

References 57 publications

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“…Nevertheless, other genes associated with alarmin-associated paracrine signaling were unchanged (S100B) or even decreased (HMGB1), reinforcing the homeostatic imbalance and the decompensated neuro-immune inflammatory status. Compromised neuronal function may derive from the decreased chemokine (C-X3-C motif) ligand 1 (CX3CL1) levels and the concomitant elevation of its receptor CX3CR1 in microglia ( p < 0.001 vs. WT mice), suggested to associate to neurodegeneration, or even to protection [ 52 ]. Increased levels of synaptophysin and decreased Dlg4, which encodes for PSD-95 ( p < 0.001 vs. WT mice, for both), may be also due to compensatory mechanisms in deficient synaptic transmission.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Vaz

Vizinha

Morais

et al. 2021

IJMS

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miRNA(miR)-124 is an important regulator of neurogenesis, but its upregulation in SOD1G93A motor neurons (mSOD1 MNs) was shown to associate with neurodegeneration and microglia activation. We used pre-miR-124 in wild-type (WT) MNs and anti-miR-124 in mSOD1 MNs to characterize the miR-124 pathological role. miR-124 overexpression in WT MNs produced a miRNA profile like that of mSOD1 MNs (high miR-125b; low miR-146a and miR-21), and similarly led to early apoptosis. Alterations in mSOD1 MNs were abrogated with anti-miR-124 and changes in their miRNAs mostly recapitulated by their secretome. Normalization of miR-124 levels in mSOD1 MNs prevented the dysregulation of neurite network, mitochondria dynamics, axonal transport, and synaptic signaling. Same alterations were observed in WT MNs after pre-miR-124 transfection. Secretome from mSOD1 MNs triggered spinal microglia activation, which was unno-ticed with that from anti-miR-124-modulated cells. Secretome from such modulated MNs, when added to SC organotypic cultures from mSOD1 mice in the early symptomatic stage, also coun-teracted the pathology associated to GFAP decrease, PSD-95 and CX3CL1-CX3CR1 signaling im-pairment, neuro-immune homeostatic imbalance, and enhanced miR-124 expression levels. Data suggest that miR-124 is implicated in MN degeneration and paracrine-mediated pathogenicity. We propose miR-124 as a new therapeutic target and a promising ALS biomarker in patient sub-populations.

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Section: Resultsmentioning

confidence: 99%

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Vaz

Vizinha

Morais

et al. 2021

IJMS

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“…The haploinsufficiency of MyD88 strongly decreases the transcription of cx3cr1 , chi3l3 , tnf‐α , and il‐1β genes in microglia of our APP/PS1‐transgenic mice. Cx3Cr1 expression is up‐regulated in the brain of AD patients or animal models (Gonzalez‐Prieto et al, 2021). Deficiency of Cx3Cr1 decreases cerebral Aβ in various APP‐transgenic mice (Hickman, Allison, Coleman, Kingery‐Gallagher, & El Khoury, 2019; Lee et al, 2010; Z. Liu, Condello, Schain, Harb, & Grutzendler, 2010).…”

Section: Discussionmentioning

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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“…In fact, we observed that neuronal secretion of CX3CL1 in response to NA reduced the production of nitrites in microglia [ 137 ]. Furthermore, the administration of the NA reuptake inhibitor reboxetine induced the expression of the CX3CL1 receptor CX3CR1 in the brain cortex of WT and 5xFAD mice [ 138 ]. CX3CR1 was also found to be elevated in human brain cortices from AD patients and in 5xFAD mice.…”

Section: Direct Effects Of Noradrenalinementioning

confidence: 99%

Noradrenaline in Alzheimer’s Disease: A New Potential Therapeutic Target

Gutiérrez

Russo

Novellino

et al. 2022

IJMS

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A growing body of evidence demonstrates the important role of the noradrenergic system in the pathogenesis of many neurodegenerative processes, especially Alzheimer’s disease, due to its ability to control glial activation and chemokine production resulting in anti-inflammatory and neuroprotective effects. Noradrenaline involvement in this disease was first proposed after finding deficits of noradrenergic neurons in the locus coeruleus from Alzheimer’s disease patients. Based on this, it has been hypothesized that the early loss of noradrenergic projections and the subsequent reduction of noradrenaline brain levels contribute to cognitive dysfunctions and the progression of neurodegeneration. Several studies have focused on analyzing the role of noradrenaline in the development and progression of Alzheimer’s disease. In this review we summarize some of the most relevant data describing the alterations of the noradrenergic system normally occurring in Alzheimer’s disease as well as experimental studies in which noradrenaline concentration was modified in order to further analyze how these alterations affect the behavior and viability of different nervous cells. The combination of the different studies here presented suggests that the maintenance of adequate noradrenaline levels in the central nervous system constitutes a key factor of the endogenous defense systems that help prevent or delay the development of Alzheimer’s disease. For this reason, the use of noradrenaline modulating drugs is proposed as an interesting alternative therapeutic option for Alzheimer’s disease.

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Microglial CX3CR1 production increases in Alzheimer's disease and is regulated by noradrenaline

Cited by 22 publications

References 57 publications

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

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

Noradrenaline in Alzheimer’s Disease: A New Potential Therapeutic Target

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