Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome

Hui, Chin Wai; St‐Pierre, Marie‐Kim; Detuncq, Jérôme; Aumailley, Lucie; Dubois, Mathilde; Couture, Vincent; Skuk, Daniel; Marette, André; Tremblay, Jacques P.; Lebel, Michel; Tremblay, Marie‐Ève

doi:10.1016/j.bbi.2018.06.007

Cited by 40 publications

(31 citation statements)

References 86 publications

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“…All reported data on graphs represent mean ± standard error of the mean (SEM). For microglial density, distribution and morphology studies n = animal, for phagocytosis and EM studies n = cell, process, or dendrite [39,43].…”

Section: Discussionmentioning

confidence: 99%

“…Immunofluorescent staining for light microscopy was performed as described previously with minor modifications to adapt the protocol for free-floating sections [39]. Briefly, free-floating sections were washed in PBS, incubated in 0.1M citrate buffer for 15 minutes at 90 °C, washed, and incubated for 1 hour using block of 2% normal donkey serum in PBS containing 0.2% Triton X-100.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Profiles of neurons, synaptic elements, and microglia were identified according to well-established criteria [42] Microglia were identified both by their IBA1 immunoreactivity as well as their association with extracellular space pockets, distinctive long stretches of endoplasmic reticulum (ER), and small elongated nucleus [37]. Between 7 and 11 microglial cell bodies (imaged using magnifications between 4800x and 9300x) and 70 to 100 microglial cell processes (imaged at 9300x) profiles per animal were photographed using an ORCA-HR digital camera and analyzed by blinded researchers using ImageJ as previously described [39,43].…”

Section: Temmentioning

confidence: 99%

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Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology

Savage

St‐Pierre

Carrier

et al. 2019

Preprint

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Background: Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain's resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD.Methods: To provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10 and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam-scanning electron microscopy.Results: At 3 weeks of age, prior to any known motor deficits, light microscopy studies revealed that microglia in R6/2 animals displayed a mature morphological phenotype, not reached by microglia in WT animals until 7-10 weeks of age. Microglia from R6/2 mice across all ages investigated also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week old R6/2 mice made fewer contacts with synaptic structures than those of 3-week old R6/2 mice and age-matched WT littermates. While synaptic density was not affected by genotype at 3 weeks of age, it only increased with maturation in WT mice between 3 and 10 weeks of age. The location of synapses was lastly modified from targeting dendritic spines to trunks at 3 and 10 weeks of age in R6/2 mice versus WT controls.Conclusions: These findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Temmentioning

confidence: 99%

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Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology

Savage

St‐Pierre

Carrier

et al. 2019

Preprint

Self Cite

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“…In addition to the distinct microglial morphological properties that were revealed by light or fluorescence microscopy, the use of high spatial‐resolution electron microscopy (EM) uncovered alongside to the typical microglia the occurrence of microglia filled by cellular debris, akin to the fat granule or gitter cells initially described by Río‐Hortega (), during aging, age‐related loss of sensory function, and Werner syndrome in mice (Tremblay et al , ; Hui et al , ). Recently, EM also allowed to identify an ultrastructurally distinct microglial population, the “dark” microglia, in the adult and aged mouse hippocampus (CA1 region and dentate gyrus), cerebral cortex, amygdala, and hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

Microglial subtypes: diversity within the microglial community

et al. 2019

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Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.

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“…Optical values were normalized over actin. Open field was performed to evaluate anxiety-like behaviors, exploration habits, and also locomotor activity as described by Hui et al (28). Each mouse was individually recorded and analyzed by the ANY-maze system.…”

Section: Quantification Was Done By Determining the Integrative Densimentioning

confidence: 99%

Muramyl dipeptide mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer’s disease

Malekia

Cisbania

Plante

et al. 2020

Preprint

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Background Muramyl dipeptide (MDP) is a component derived from minimal peptidoglycan motif from bacteria and it is a ligand for the NOD2 receptor. Peripheral administration of MDP converts Ly6Chigh into Ly6Clow monocytes. Previously we have shown that Ly6Clow monocytes play crucial roles in the pathology of a mouse model of Alzheimer’s disease (AD). However, medications with mild immunomodulatory effects that solely target specific monocyte subsets, without triggering microglial activation are rare. Methods 3-months old APPswe/PS1 transgenic male mice and age-matched C57BL/6J mice were used for high frequency (2-times/week) over 6-months and low frequency (once a week) over a 3-months period of intraperitoneally MDP (10 mg/kg) administrations. Flow cytometry analysis of monocyte subsets in blood, behavioral and post mortem analyses were performed. Two-photon microscopy using APP/PS1/CX3CR1gfp/+ mice were conducted to study vascular Aβ clearance by Ly6Clow monocytes upon MDP administration.Results The treatment improved cognitive declines, increased expression levels of postsynaptic density protein 95 (PSD95) andlow density lipoprotein receptor-related protein 1 (LRP1), which are involved in synaptic plasticity and amyloid beta (Aβ) elimination, respectively. In addition, we found monocyte chemoattractant protein-1(MCP-1) levels significantly increased, whereas intercellular adhesion molecule-1(ICAM-1) significantly decreased and microglial marker (Iba1) did not change in treatment group compared to the control. In parallel, we discovered elevated cyclooxygenase-2 (COX2) expression levels in the treated group, which might be a positive factor for synaptic activity. Following MDP treatment, intravital two-photon microscopy demonstrated that Ly6Clow monocytes are recruited into the brain vasculature in APP but not wild type mice, and they are able to pick up Aβ peptides. Conclusions Our results demonstrate that MDP is beneficial in both the early phase and to some extent later phases of the pathology in the mouse model of AD. These data open the way for potential MDP-based medications for AD.

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Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome

Cited by 40 publications

References 86 publications

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology

Microglial subtypes: diversity within the microglial community

Muramyl dipeptide mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer’s disease

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