Serge Rivest

Laval University, Quebec City, Quebec, Canada

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Publications (250)1348.01 Total impact


  • No preview · Article · Jan 2016 · Brain
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    Peter Theriault · Maude Bordeleau · Serge Rivest

    Full-text · Article · Jan 2016
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    Peter Thériault · Ayman ElAli · Serge Rivest
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia among elderly population worldwide. AD is mainly characterized by the accumulation and aggregation of amyloid-beta (Aβ) peptides, which form over time senile plaques in the brain parenchyma and microaggregates in the cerebral vasculature 1. Unfortunately, the exact causes of the disease are still unclear. Several studies have underlined the implication of the neurovascular unit, which includes pericytes that regulates the blood-brain barrier (BBB) parameters, in AD pathogenesis 2. However, it is not known if its dysfunction is a cause or a consequence of neurodegenerative cascades that leads to AD. In attempt to answer this question, we investigated the role of high fat diet and its interaction with age, which are two major risk factors associated to AD 3 , in neuroinflammation and AD progression. Three and 12 months old APPswe/PS1 mice, a transgenic mouse model of AD, were fed for 4 months with a " western diet " (WD) containing 42% kcal from fat, or " normal diet " (ND) for control groups. Animals were assessed at 7 and 16 months old. Neurobehavioral tests reveal that WD accelerates the cognitive decline in APPswe/PS1 mice, but without affecting the Aβ plaques loading in the brain parenchyma. However, WD exacerbates the age-associated loss of synaptic plasticity, which strongly correlates with cognitive deficits observed in WD-fed animals. Moreover, WD increases total monocytes frequencies and oxidized-LDL levels in the blood circulation, thus promoting a systemic pro-inflammatory environment. Importantly, WD increases soluble Aβ 1-40 levels and promotes oxidative stress via the accumulation of malondialdehyde (MDA), specifically in the cerebral microvasculature. These phenomenons were accompanied by the dysfunction of pericytes, but do not affect the permeability of the BBB. Finally, an in vitro assay reveals that the combination of Aβ 1-40 and MDA reduces the metabolic activity of pericytes, thus indicating their dysfunction, which confirms previous in vivo observations.
    Full-text · Conference Paper · Dec 2015
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    ABSTRACT: The central nervous system (CNS) is a very unique system with multiple features that differentiate it from systemic tissues. One of the most captivating aspects of its distinctive nature is the presence of the blood brain barrier (BBB), which seals it from the periphery. Therefore, to preserve tissue homeostasis, the CNS has to rely heavily on resident cells such as microglia. These pivotal cells of the mononuclear lineage have important and dichotomous roles according to various neurological disorders. However, certain insults can overwhelm microglia as well as compromising the integrity of the BBB, thus allowing the infiltration of bone marrow-derived macrophages (BMDMs). The use of myeloablation and bone marrow transplantation allowed the generation of chimeric mice to study resident microglia and infiltrated BMDM separately. This breakthrough completely revolutionized the way we captured these 2 types of mononuclear phagocytic cells. We now realize that microglia and BMDM exhibit distinct features and appear to perform different tasks. Since these cells are central in several pathologies, it is crucial to use chimeric mice to analyze their functions and mechanisms to possibly harness them for therapeutic purpose. This review will shed light on the advent of this methodology and how it allowed deciphering the ontology of microglia and its maintenance during adulthood. We will also compare the different strategies used to perform myeloablation. Finally, we will discuss the landmark studies that used chimeric mice to characterize the roles of microglia and BMDM in several neurological disorders.
    No preview · Article · Oct 2015 · Biochimica et Biophysica Acta
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    ABSTRACT: Alzheimer's disease (AD) is the leading cause of dementia among elderly population. AD is characterized by the accumulation of beta-amyloid (Aβ) peptides, which aggregate over time to form amyloid plaques in the brain. Reducing soluble Aβ levels and consequently amyloid plaques constitute an attractive therapeutic avenue to, at least, stabilize AD pathogenesis. The brain possesses several mechanisms involved in controlling cerebral Aβ levels, among which are the tissue-plasminogen activator (t-PA)/plasmin system and microglia. However, these mechanisms are impaired and ineffective in AD. Here we show that the systemic chronic administration of recombinant t-PA (Activase(®) rt-PA) attenuates AD-related pathology in APPswe/PS1 transgenic mice by reducing cerebral Aβ levels and improving the cognitive function of treated mice. Interestingly, these effects do not appear to be mediated by rt-PA-induced plasmin and matrix metalloproteinases 2/9 (MMP2/9) activation We observed that rt-PA essentially mediated a slight transient increase in the frequency of patrolling monocytes in the circulation and stimulated microglia in the brain to adopt a neuroprotective phenotype, both of which contribute to Aβ elimination. Our study unraveled a new role of rt-PA in maintaining the phagocytic capacity of microglia without exacerbating the inflammatory response and therefore might constitute an interesting approach to stimulate the key populations of cells involved in Aβ clearance from the brain.Neuropsychopharmacology accepted article preview online, 09 September 2015. doi:10.1038/npp.2015.279.
    Full-text · Article · Sep 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
  • Ayman ElAli · Serge Rivest
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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting elderly people worldwide, which is mainly characterized by cerebral amyloid-beta (Aβ) plaque deposition and neurofibrillary tangle formation. The interest in microglia arose from the overwhelming experimental evidence that outlined a key role of neuroinflammation in AD pathology. Microglia constitute the powerhouse of the innate immune system in the brain. It is now widely accepted that microglia are myeloid-derived cells that infiltrate the developing brain at the early embryonic stages, and acquire a highly ramified phenotype postnatally. Microglia use these dynamic ramifications as sentinels to sense and detect any occurring alteration in brain homeostasis. Once a danger signal is detected, microglia get activated by acquiring a less ramified phenotype, and mount adequate responses that range from phagocyting cell debris to secreting inflammatory and trophic factors. Earlier reports have demonstrated, unequivocally, that microglia surround Aβ plaques and internalize Aβ microaggregates. However, the implication of these observations in AD pathology, and consequently treatment, is still a matter of debate. Nonetheless, targeting the activity of these cells constituted a convergent point in this debate. Unfortunately, the conflicting experimental findings obtained following the modulation of microglial activity in AD, further fueled the debate. This review aims at providing an overview regarding what we know about the implication of microglia in AD pathology and treatment. The emerging role of monocytes is also discussed. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Aug 2015 · Brain Behavior and Immunity
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    Serge Rivest

    Preview · Article · Jun 2015 · Oncotarget
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    Peter Thériault · Ayman ElAli · Serge Rivest
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    ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting older people worldwide. It is a progressive disorder mainly characterized by the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles within the brain parenchyma. It is now well accepted that neuroinflammation constitutes an important feature in AD, wherein the exact role of innate immunity remains unclear. Although innate immune cells are at the forefront to protect the brain in the presence of toxic molecules including Aβ, this natural defense mechanism seems insufficient in AD patients. Monocytes are a key component of the innate immune system and they play multiple roles, such as the removal of debris and dead cells via phagocytosis. These cells respond quickly and mobilize toward the inflamed site, where they proliferate and differentiate into macrophages in response to inflammatory signals. Many studies have underlined the ability of circulating and infiltrating monocytes to clear vascular Aβ microaggregates and parenchymal Aβ deposits respectively, which are very important features of AD. On the other hand, microglia are the resident immune cells of the brain and they play multiple physiological roles, including maintenance of the brain's microenvironment homeostasis. In the injured brain, activated microglia migrate to the inflamed site, where they remove neurotoxic elements by phagocytosis. However, aged resident microglia are less efficient than their circulating sister immune cells in eliminating Aβ deposits from the brain parenchyma, thus underlining the importance to further investigate the functions of these innate immune cells in AD. The present review summarizes current knowledge on the role of monocytes and microglia in AD and how these cells can be mobilized to prevent and treat the disease.
    Full-text · Article · Apr 2015 · Alzheimer's Research and Therapy
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    Serge Rivest
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    ABSTRACT: In a recent paper published in Cell, Wang et al. report that deficiency of triggering receptor expressed on myeloid cells 2 (TREM2) augments amyloid β accumulation and neuronal loss in a mouse model of Alzheimer's disease. TREM2 acts as a signaling receptor involved in innate immunity for the natural clearance of this toxic protein by microglia.
    Preview · Article · Mar 2015 · Cell Research
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    ABSTRACT: An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired. © 2015 Lampron et al.
    Full-text · Article · Mar 2015 · Journal of Experimental Medicine
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    ABSTRACT: Chemokines are a family of cytokines involved in the chemotaxis of leukocytes and other target cells by binding to specific G-protein-coupled receptors on their membranes. As such, the activation of C-C chemokine receptor type 2 (CCR2) is involved in the mobilization of "inflammatory" monocytes from bone marrow and in their recruitment to the brain under inflammatory/pathological conditions. In this study, we investigated whether CCR2 signaling could affect the progression of learning deficits and hippocampal damage in a model of neonatal hypoxic-ischemic (HI) brain injury. Postnatal day 3 wild-type (WT) and CCR2 knockout (KO) mice of both sexes were subjected to the Rice-Vannucci model of neonatal hypoxia-ischemia and were followed for up to 14 weeks. HI CCR2 KO male mice were the only animals to exhibit long-term spatial learning deficits in the T-water maze task, compared to their corresponding sham-operated controls. CCR2 KO mouse pups of both sexes had a lower number of circulating monocytes, although only HI CCR2 KO male mice exhibited reduced numbers of activated macrophages/microglia in the damaged hippocampus, compared to WT mice. However, no differences were observed in hippocampal atrophy between HI CCR2 KO and HI WT mice. These results suggest that CCR2 signaling can protect neonatal mice from developing spatial learning deficits after a HI insult, in a sex-specific fashion. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Mar 2015 · Behavioural Brain Research
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    ABSTRACT: Excitotoxic cell death is a crucial mechanism through which neurodegeneration occurs in numerous pathologies of the central nervous system (CNS), such as Alzheimer disease, stroke and spinal cord injury. Toll-like receptors (TLRs) are strongly expressed on microglial cells and are key regulators of the innate immune response to neuronal damage. However, it is still unclear whether their stimulation is protective or harmful in excitotoxic contexts. In this study, we demonstrate that systemic administration of lipopolysaccharide (LPS) or Pam3CSK4 24h prior to an intrastriatal injection of kainic acid (KA) significantly protected cortical neurons in the acute phase of injury. Protection could not be detected with the TLR3 ligand poly-IC. Histological analysis revealed that microglia of LPS and Pam3CSK4 pre-conditioned group were primed to react to injury and exhibited a stronger expression of Tnf and Tlr2 mRNA. We also found that mice deficient for MyD88, a critical adaptor protein for most TLR, were more vulnerable than WT mice to KA-induced excitotoxicity at early (12h and 24h) and late (10days) time points. Finally, bone-marrow chimeric mice revealed that MyD88 signaling in CNS resident cells, but not in cells of hematopoietic origin, mediates the protective effect. This study unravels the potential of TLR2 and TLR4 agonists to induce a protective state of preconditioning against KA-mediated excitotoxicity and further highlights the beneficial role of cerebral MyD88 signaling in this context. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Feb 2015 · Brain Behavior and Immunity
  • Jean-Philippe Michaud · Serge Rivest
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    ABSTRACT: In this issue of Neuron, Chakrabarty etal. (2015) and Guillot-Sestier etal. (2015) reveal that the anti-inflammatory cytokine IL-10 inhibits Aβ clearance by microglia, worsening cognitive decline in mouse models of Alzheimer's disease (AD). These studies provide further support that pro-inflammatory signaling is an innate immune defense mechanism in AD. In this issue of Neuron, Chakrabarty etal. (2015) and Guillot-Sestier etal. (2015) reveal that the anti-inflammatory cytokine IL-10 inhibits Aβ clearance by microglia, worsening cognitive decline in mouse models of Alzheimer's disease (AD). These studies provide further support that pro-inflammatory signaling is an innate immune defense mechanism in AD.
    No preview · Article · Feb 2015 · Neuron
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    ABSTRACT: Microglia surrounds the amyloid plaques that form in the brains of patients with Alzheimer's disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, i.e., experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Brain Behavior and Immunity
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    ABSTRACT: Microglia surrounds the amyloid plaques that form in the brains of patients with Alzheimer's disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, i.e., experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline.
    Full-text · Article · Jan 2015 · Brain Behavior and Immunity
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    ABSTRACT: Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling. When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator, macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B, particularly in combination with MCSF, increased the number of oligodendrocyte precursor cells and promoted remyelination within lesions; these pro-regenerative effects were mitigated in mice treated with clodronate liposomes to reduce circulating monocytes and tissue-infiltrated macrophages. Our results have identified candidates among currently used medications as potential therapies for the repair of myelin. Copyright © 2015 the authors 0270-6474/15/351136-13$15.00/0.
    Full-text · Article · Jan 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: The relevance of surface molecules in the brain is substantial because neurons can harbor many sophisticated contacts with other cells. Surface antigens, such as cluster of differentiation (CD) molecules, deliver cellular clues coupled to glial/neuronal identity and function. Whereas CD36 and CD83 have been mainly associated with subtypes of myeloid-derived cells in the brain, CD44 was also characterized in astrocytes and neural progenitors. Cd36, Cd44, and Cd83 transcripts associate distinctly with defined murine brain circuitry, displaying varied expression levels. The known structural and functional dissimilarities between the encoded glycoproteins parallel their different patterns of expression throughout the brain, suggesting that CD molecules could play roles in specific neuronal cells other than those characterized in leukocytes. Emerging data are helping to reveal these functions, and these antigens combined with others are potential tools to sort glial or neuronal cells for performing cellular or large-scale profiling assays.
    No preview · Article · Jan 2015
  • Megan Strachan-Whaley · Serge Rivest · V Wee Yong
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    ABSTRACT: Brain-resident microglia and T lymphocytes recruited into the central nervous system both play important roles in the neuropathology of multiple sclerosis. The microglia and recruited T cells are in close proximity in lesions of multiple sclerosis and in animal models, suggesting their potential for interactions. In support, microglia and T cells express a number of molecules that permit their engagement. Here we describe the interactions between T cells and microglia and the myriad responses that can result. These interactions include antigen presentation by microglia to activate T cells, the T cell activation of microglia, their progressive stimulation of one another, and the production of injurious or neurotrophic outcomes in their vicinity. Important considerations for the future include the nature of the T helper cell subsets and the M1 and M2 polarized nature of microglia, as the interactions between different subsets likely result in particular functions and outcomes. That T cells and microglia are in proximity and that they interact in lesions in the central nervous system implicate them as modifiers of pathobiology in multiple sclerosis.
    No preview · Article · Aug 2014 · Journal of Interferon & Cytokine Research
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    ABSTRACT: After an ischemic stroke, mononuclear phagocytic cells such as microglia, macrophages, and monocytes migrate to the lesion site and coordinate an immune response. Monocytes, which are recruited from the bloodstream after ischemic brain injury, can be categorized into two subsets in mice: inflammatory and patrolling monocytes. Although inflammatory monocytes (Ly6C(hi)) seem to have a protective role in stroke progression, the impact of patrolling monocytes (Ly6C(low)) is unknown. To address the role of Ly6C(low) monocytes in stroke, we generated bone marrow chimeric mice in which their hematopoietic system was replaced by Nr4a1(-/-) cells, allowing the complete and permanent ablation of Ly6C(low) monocytes without affecting the Ly6C(hi) subset. We then subjected adult mice to cerebral hypoxia-ischemia using the Levine/Vannucci model. Functional outcomes after stroke such as body weight change, neurologic score, motor functions and spatial learning were not affected. Moreover, depletion in Ly6C(low) monocytes did not change significantly the total infarct size, cell loss, atrophy, the number, or the activation state of microglia/macrophages at the lesion site. These data suggest that Ly6C(low) patrolling monocytes are redundant in the progression and recovery of ischemic stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.80.
    No preview · Article · Apr 2014 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    ABSTRACT: Excitotoxicity underlies neuronal death in many neuropathological disorders, such as Alzheimer's disease and multiple sclerosis. In murine models of these diseases, disruption of CX3CR1 signaling has thus far generated data either in favor or against a neuroprotective role of this crucial regulator of microglia and monocyte functions. In this study, we investigated the recruitment of circulating PU.1-expressing cells following sterile excitotoxicity and delineated the CX3CR1-dependent neuroprotective functions of circulating monocytes versus that of microglia in this context. WT, Cx3cr1-deficient and chimeric mice were subjected to a sterile excitotoxic insult via an intrastriatal injection of kainic acid (KA), a conformational analog of glutamate. Following KA administration, circulating monocytes physiologically engrafted the brain and selectively accumulated in the vicinity of excitotoxic lesions where they gave rise to activated macrophages depicting strong Iba1 and CD68 immunoreactivity 7 days post-injury. Monocyte-derived macrophages completely vanished upon recovery and did thus not permanently seed the brain. Furthermore, Cx3cr1 deletion significantly exacerbated neuronal death, behavioral deficits and activation of microglia cells following sterile excitotoxicity. Cx3cr1 disruption also markedly altered the blood levels of patrolling monocytes 24 h after KA administration. The specific elimination of patrolling monocytes using Nr4a1 (-/-) chimeric mice conditioned with chemotherapy provided direct evidence that these circulating monocytes are essential for neuroprotection. Taken together, these data support a beneficial role of CX3CR1 signaling during excitotoxicity and highlight a novel and pivotal role of patrolling monocytes in neuroprotection. These findings open new research and therapeutic avenues for neuropathological disorders implicating excitotoxicity.
    Full-text · Article · Apr 2014 · Brain Structure and Function

Publication Stats

17k Citations
1,348.01 Total Impact Points

Institutions

  • 1990-2015
    • Laval University
      • • Department of Molecular Medicine
      • • Faculty of Medicine
      • • Department of Medicine
      Quebec City, Quebec, Canada
  • 2005-2013
    • Centre Hospitalier Universitaire de Québec (CHUQ)
      Québec, Quebec, Canada
  • 1993-2012
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 1989-2009
    • Université du Québec
      Quebec City, Quebec, Canada
  • 2001
    • McGill University
      • Centre for Research in Neuroscience
      Montréal, Quebec, Canada
  • 1991-1994
    • Salk Institute
      • Clayton Foundation Laboratories for Peptide Biology
      لا هویا, California, United States