Serge Rivest

Laval University, Québec, Quebec, Canada

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Publications (219)1158.35 Total impact

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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.
    08/2014; 34(8):615-22.
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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.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2014; · 5.46 Impact Factor
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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.
    Brain Structure and Function 04/2014; · 7.84 Impact Factor
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    ABSTRACT: The blood-nerve barrier (BNB) is a selectively permeable barrier that creates an immunologically and biochemically privileged space for peripheral axons and supporting cells. The breakdown of the BNB allows access of blood-borne (hematogenous) cells and molecules to the endoneurium to engage in the local inflammatory cascade. This process was examined in a mouse model of trauma associated neuropathic pain. The impact of nerve injury triggered-opening of the BNB in the development of chronic pain behavior was investigated. Partial ligation of the sciatic nerve led to a long-lasting disruption of the BNB distal to the site of injury. Vascular endothelial growth factor (VEGF) was expressed by resident macrophages after nerve injury. Intraneural injection of VEGF decreased mechanical thresholds while opening the BNB. Serum from nerve injured or LPS treated animals elicited mechanical allodynia in naive animals, when allowed to bypass the BNB by intraneural injection. Intraneural injection of fibrinogen, a clotting protein in plasma which was found to deposit in the nerve following nerve injury, also produced a decrease in mechanical thresholds when introduced into naive nerves. These results demonstrate that blood-borne molecules may play a role in the generation of neuropathic pain, suggesting that pain may be driven from infection or injury, at a distance from the nervous system. Furthermore, the breakdown of the BNB in neuropathic conditions was exploited to permit the entry of analgesic molecules that typically cannot pass the BNB, such as ProToxin-II, a BNB impermeable Nav1.7 inhibitor. Therapeutics utilizing this mechanism could have selective access to injured nerves over healthy tissues.
    Pain 02/2014; · 5.64 Impact Factor
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    Ayman Elali, Peter Thériault, Serge Rivest
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    ABSTRACT: Neurons are extremely vulnerable cells that tightly rely on the brain's highly dynamic and complex vascular network that assures an accurate and adequate distribution of nutrients and oxygen. The neurovascular unit (NVU) couples neuronal activity to vascular function, controls brain homeostasis, and maintains an optimal brain microenvironment adequate for neuronal survival by adjusting blood-brain barrier (BBB) parameters based on brain needs. The NVU is a heterogeneous structure constituted by different cell types that includes pericytes. Pericytes are localized at the abluminal side of brain microvessels and contribute to NVU function. Pericytes play essential roles in the development and maturation of the neurovascular system during embryogenesis and stability during adulthood. Initially, pericytes were described as contractile cells involved in controlling neurovascular tone. However, recent reports have shown that pericytes dynamically respond to stress induced by injury upon brain diseases, by chemically and physically communicating with neighboring cells, by their immune properties and by their potential pluripotent nature within the neurovascular niche. As such, in this paper, we would like to review the role of pericytes in NVU remodeling, and their potential as targets for NVU repair strategies and consequently neuroprotection in two pathophysiologically distinct brain disorders: ischemic stroke and Alzheimer's disease (AD).
    International Journal of Molecular Sciences 01/2014; 15(4):6453-74. · 2.46 Impact Factor
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    Marc-André Bellavance, Serge Rivest
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    ABSTRACT: In response to physiological and psychogenic stressors, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates the systemic release of glucocorticoids (GCs). By virtue of nearly ubiquitous expression of the GC receptor and the multifaceted metabolic, cardiovascular, cognitive, and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state. GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms. These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory, and hematological disorders. The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions. Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone. In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment. We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.
    Frontiers in Immunology 01/2014; 5:136.
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    ABSTRACT: Microglia are the brain-resident macrophages tasked with the defense and maintenance of the central nervous system (CNS). The hematopoietic origin of microglia has warranted a therapeutic potential for the hematopoietic system in treating diseases of the CNS. However, migration of bone marrow-derived cells (BMDC) into the CNS is a marginal event under normal, healthy conditions. A busulfan-based chemotherapy regimen was used for bone marrow transplantation in wild-type mice before subjecting them to a hypoxic-ischemic brain injury or in APP/PS1 mice prior to the formation of amyloid plaques. The cells were tracked and analyzed throughout the development of the pathology. The efficacy of a preventive macrophage colony-stimulating factor (M-CSF) treatment was also studied to highlight the effects of circulating monocytes in hypoxic-ischemic brain injury. Such an injury induces a strong migration of BMDC into the CNS, without the need for irradiation. These migrating cells do not replace the entire microglial pool but rather are confined to the sites of injury for several weeks, suggesting that they could perform specific functions. M-CSF showed neuroprotective effects as a preventive treatment. In APP/PS1 mice, the formation of amyloid plaques was sufficient to induce the entry of cells into the parenchyma, though in low numbers. This study confirms that BMDC infiltrate the CNS in animal models for stroke and Alzheimer's disease and that peripheral cells can be targeted to treat affected regions of the CNS. J. Comp. Neurol. 521:3863-3876, 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 12/2013; 521(17):Spc1. · 3.66 Impact Factor
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    ABSTRACT: Background The Blood–brain barrier (BBB) controls brain supply with oxygen and nutrients, and protects the brain from toxic metabolites, such as beta-amyloid (Aβ) peptides. The neurovascular unit (NVU) couples vascular and neuronal functions by controlling BBB parameters based on brain needs. As such, NVU/BBB dysfunction, associated to irregularities in cerebral blood flow (CBF), has been proposed to contribute in the pathogenesis of Alzheimer’s disease (AD), mainly by impairing cerebral Aβ clearance. However, the spatiotemporal contribution of the NVU/BBB in the neurodegenerative cascades remains elusive. Results By using C57Bl6/J mice subjected to right common carotid artery (rCCA) permanent ligation in order to induce mild chronic cerebral hypoperfusion, we show here that cerebral hypoperfusion induced NVU dysfunction by reducing ABCB1 protein expression in brain capillaries. ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 (GSK3β) activation, which decreased β-catenin nuclear abundance. Moreover, cerebral hypoperfusion triggered early vascular deposition of peripherally applied human Aβ1-42 peptides, which has shifted from highly vascular to the parenchyma 6 weeks later, forming small stable Aβ deposits. Hypoperfusion induced a deregulation in glucose metabolism, as brain reperfusion, or the administration of a high dose of glucose, diminished GSK3β activation, recuperated β-catenin nuclear abundance, reestablished ABCB1 protein expression, and prevented Aβ vascular early deposition. These results demonstrate that mild chronic cerebral hypoperfusion creates a metabolically deregulated microenvironment, thus triggering the brain entry and aggregation of peripherally applied human Aβ1-42 peptides. Conclusion Our study offers new insights on the initiation of the neurodegenerative cascades, which could be valuable in developing adequate treatment strategies.
    Acta Neuropathologica Communications. 11/2013;
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    ABSTRACT: For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases. Moreover, it is now understood that the barriers of the brain are not uniform in their interactions with the circulating immune cells. The implications of these new findings to the basic understanding of CNS repair processes, brain aging, and a wide spectrum of CNS disorders, including acute injuries, Rett syndrome, Alzheimer's disease, and multiple sclerosis, will be discussed.
    Journal of Neuroscience 11/2013; 33(45):17587-96. · 6.91 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) that is assumed to result from impaired elimination of this neurotoxic peptide. Most patients with AD also exhibit cerebral amyloid angiopathy, which consists of Aβ deposition within the cerebral vasculature. The contribution of monocytes in AD has so far been limited to macrophage precursors. In this study, we aimed to investigate whether circulating monocytes could play a role in the elimination of Aβ. With live intravital two-photon microscopy, we demonstrate that patrolling monocytes are attracted to and crawl onto the luminal walls of Aβ-positive veins, but not on Aβ-positive arteries or Aβ-free blood vessels. Additionally, we report the presence of crawling monocytes carrying Aβ in veins and their ability to circulate back into the bloodstream. Selective removal of Ly6C(lo) monocytes in APP/PS1 mice induced a significant increase of Aβ load in the cortex and hippocampus. These data uncover the ability of Ly6C(lo) monocytes to naturally target and eliminate Aβ within the lumen of veins and constitute a potential therapeutic target in AD.
    Cell Reports 11/2013; · 7.21 Impact Factor
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    ABSTRACT: Inflammatory mechanisms contribute substantially to secondary tissue injury after brain ischemia. Regulatory T cells (Tregs) are key endogenous modulators of postischemic neuroinflammation. We investigated the potential of histone deacetylase inhibition (HDACi) to enhance Treg potency for experimental stroke in mice. HDACi using trichostatin A increased the number of Tregs and boosted their immunosuppressive capacity and interleukin (IL)-10 expression. In vivo treatment reduced infarct volumes and behavioral deficits after cortical brain ischemia, attenuated cerebral proinflammatory cytokine expression, and increased numbers of brain-invading Tregs. A similar effect was obtained using tubastatin, a specific inhibitor of HDAC6 and a key HDAC in Foxp3 regulation. The neuroprotective effect of HDACi depended on the presence of Foxp3(+) Tregs, and in vivo and in vitro studies showed that the anti-inflammatory cytokine IL-10 was their main mediator. In summary, modulation of Treg function by HDACi is a novel and potent target to intervene at the center of neuroinflammation. Furthermore, this novel concept of modulating endogenous immune mechanisms might be translated to a broad spectrum of diseases, including primary neuroinflammatory and neurodegenerative disorders.
    Journal of Neuroscience 10/2013; 33(44):17350-62. · 6.91 Impact Factor
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    ABSTRACT: La maladie d'Alzheimer (MA) est une maladie neurodégénérative caractérisée par l'accumulation extracellulaire du peptide β-amyloïde (Aβ), formant des dépôts dans le parenchyme et la vasculature du système nerveux central (SNC). Des études ont suggéré que cette accumulation serait associée à un défaut dans le processus d'élimination de l'Aβ. Il n'y a présentement aucun traitement curatif de la maladie. Il a été proposé que la barrière hémato-encéphalique (BHE) jouerait un rôle crucial dans l'élimination des peptides d'Aβ, et conséquemment sur la réduction des dépôts dans le cerveau. ABCB1 est un transporteur de type « ATP-binding cassette » (ABC) exprimé du côté luminal de l'endothélium cérébral, qui contribue à l'élimination des éléments toxiques. Chez la souris APP/PS1, un modèle murin de la MA, le traitement chronique avec un dérivé détoxifié du Lipopolysaccharide (LPS), le Monophosphoryl Lipid A (MPL), a démontré une réduction des dépôts d'Aβ au cerveau par l'activation du « Toll-Like Receptor 4 » (TLR4). Il est reconnu que les cellules endothéliales cérébrales expriment le TLR4. Afin de mieux comprendre l'effet du MPL sur la fonctionnalité de la BHE et son impact sur la réduction des dépôts, nous avons étudié l'impact de l'administration systémique d'une seule dose de MPL sur l'expression d'ABCB1 et l'élimination des peptides d'Aβ. Nous avons observé que l'expression d'ABCB1 était augmentée de façon TLR4-dépendante, favorisant ainsi l'élimination de l'Aβ. Nos résultats démontrent un rôle jusqu'à maintenant inconnu de l'activation de TLR4 par le MPL au niveau de la BHE, pouvant ainsi contribuer à la détoxification du cerveau.
    Journée de la médecine moléculaire, Faculté de Médecine, Université Laval; 10/2013
  • Gaëlle Naert, Serge Rivest
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by intracellular neurofibrillary tangle formation and extracellular amyloid-β (Aβ) deposition. To date, microglia seem to act as double-edged swords, being either beneficial (e.g. clearance of Aβ) or detrimental (e.g. secretion of neurotoxic factors) in AD. Following a rather intense debate on the question, a consensus has emerged that microglia can renew themselves via proliferation of already differentiated microglia as well as via the de novo recruitment of monocytes of mouse models of AD. However, recent advances suggest distinct function for resident and bone marrow-derived microglia (BMDM), and have emphasized the neuroprotective functions of BMDM. BMDM is the only subset of cells that restrict cerebral amyloidosis in the AD brain, which has been recently attributed to CCR2(+) monocytes. Moreover, an impaired recruitment of CCR2(+) monocytes has been reported in AD patients, as seen from the CCR2(+) monocytopenia found in the bloodstream and BM. The present review summarizes the current knowledge on the roles and dysfunctions of CCR2(+) monocytes in AD and their potential as key therapeutic targets.
    Journal of Molecular Cell Biology 07/2013; · 7.31 Impact Factor
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    ABSTRACT: Hypoxia-ischemia is a common cause of neurological impairments in newborns, but little is known about how neuroinflammation contributes to the long-term outcome after a perinatal brain injury. In this study, we investigated the role of the fractalkine receptor chemokine CX3C motif receptor 1 (CX3CR1) and of toll-like receptor (TLR) signaling after a neonatal hypoxic-ischemic brain injury. Mice deficient in the TLR adaptor proteins Toll/interleukin-1 receptor-domain-containing adaptor protein inducing interferon β (TRIF) or myeloid differentiation factor-88 (MyD88) and CX3CR1 knock-out (KO) mice were subjected to hypoxia-ischemia at postnatal day 3. In situ hybridization was used to evaluate the expression of TLRs during brain development and after hypoxic-ischemic insults. Behavioral deficits, hippocampal damage, reactive microgliosis, and subplate injury were compared among the groups. Although MyD88 KO mice exhibited no differences from wild-type animals in long-term structural and functional outcomes, TRIF KO mice presented a worse outcome, as evidenced by increased hippocampal CA3 atrophy in males and by the development of learning and motor deficits in females. CX3CR1-deficient female mice showed a marked increase in brain damage and long-lasting learning deficits, whereas CX3CR1 KO male animals did not exhibit more brain injury than wild-type mice. These data reveal a novel, gender-specific protective role of TRIF and CX3CR1 signaling in a mouse model of neonatal hypoxic-ischemic brain injury. These findings suggest that future studies seeking immunomodulatory therapies for preterm infants should consider gender as a critical variable and should be cautious not to abrogate the protective role of neuroinflammation.
    Journal of Neuroscience 07/2013; 33(28):11556-11572. · 6.91 Impact Factor
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    ABSTRACT: Microglia are the brain resident macrophages tasked with the defense and maintenance of the central nervous system (CNS). The hematopoietic origin of microglia has warranted a therapeutic potential for the hematopoietic system in treating diseases of the CNS. However, migration of bone marrow derived cells into the CNS is a marginal event under normal healthy conditions. A busulfan-based chemotherapy regimen was used for bone marrow transplantation in WT mice before subjecting them to a hypoxic-ischemic brain injury or in APP/PS1 mice prior to the formation of amyloid plaques. The cells were tracked and analyzed throughout the development of the pathology. The efficacy of a preventive M-CSF treatment was also studied to highlight the effects of circulating monocytes in hypoxic-ischemic brain injury. Such an injury induces a strong migration of BMDC into the CNS, without the need for irradiation. These migrating cells do not replace the entire microglia pool but are rather confined to the sites of injury for several weeks, suggesting that they could perform specific functions. M-CSF showed neuroprotective effects as a preventive treatment. In APP/PS1 mice, the formation of amyloid plaques was sufficient to induce the entry of cells into the parenchyma, though in low numbers. This study confirms that bone marrow-derived cells infiltrate the CNS in animal models for stroke and Alzheimer's disease and that peripheral cells can be targeted to treat affected regions of the CNS. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 05/2013; · 3.66 Impact Factor
  • Antoine Lampron, Ayman Elali, Serge Rivest
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    ABSTRACT: The concept of the CNS as an immune-privileged organ has led to a common misunderstanding that it is not an active immunological organ, guarded from its surroundings by the blood-brain barrier (BBB). Recent advances in this field clearly demonstrate that the CNS is a highly immunologically active organ, with complex immune responses mostly based on innate immune processes. Such responses implicate a continuum of heterogeneous cell types both inside the CNS, in the periphery, and at their interface, the BBB. This Review aims to discuss the importance of the BBB as the first line of defense against brain infections and injuries of the CNS and the main molecular mechanisms involved in the control of the innate immune system of the CNS. We also review the central role of the neurovascular unit in diseases of the CNS and how it can be targeted for novel therapeutic strategies.
    Neuron 04/2013; 78(2):214-32. · 15.77 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD), dementia and cognitive impairment in later life are commonly associated with a mixed set of pathologies, which are frequently accompanied by local and systemic inflammation. Conflicting observations have made understanding the relative importance of innate and adaptive immune processes dif-ficult in such pathologies. However, clini-cal trials using immunization, monoclonal antibodies or anti-inflammatory medica-tion have produced disappointing results in treating AD [1]. This suggests a need to change focus. Recent data suggest that monocytes and microglia, the main innate immune defense of the CNS, may aid the clearance of b-amyloid (Ab) deposits in the brain by recruiting macrophages to the affected areas. This may represent a novel strategy for intervention.
    Neurodegenerative Disease Management. 02/2013; 3(1):9-12.
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid β (Aβ) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aβ accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aβ may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APP(swe)/PS1 mice. MPL treatment led to a significant reduction in Aβ load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.
    Proceedings of the National Academy of Sciences 01/2013; · 9.81 Impact Factor
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    Ayman Elali, Serge Rivest
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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects elderly persons, evolving with age to reach severe cognitive impairment. Amyloid deposits and neurofibrillary tangles constitute the main pathological hallmarks of AD. Amyloid deposits are initiated by the excessive production and accumulation of beta-amyloid (Aβ) peptides in the brain. The dysfunction of the Neurovascular Unit (NVU) has been proposed to be causative in AD development, due to an impaired clearance of Aβ from the brain. Cells forming the NVU express several Adenosine Triphosphate ATP-Binding Cassette (ABC) transporters, among which ABCB1 and ABCA1 play an important role in Aβ processing. The drug transporter ABCB1 directly transports Aβ from the brain into the blood circulation, whereas the cholesterol transporter ABCA1 neutralizes Aβ aggregation capacity in an Apolipoprotein E (ApoE)-dependent manner, facilitating Aβ subsequent elimination from the brain. In the present minireview, we will summarize the contribution of ABCB1, and ABCA1 at the NVU in Aβ clearance. Moreover, we will outline and discuss the possible collaboration of ABCB1, and ABCA1 at the NVU in mediating an efficient clearance of Aβ from the brain.
    Frontiers in Physiology 01/2013; 4:45.
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    ABSTRACT: Excitotoxicity is a major component of neurodegenerative diseases and is typically accompanied by an inflammatory response. Cytokines IL-1alpha and IL-1beta are key regulators of this inflammatory response and modulate the activity of numerous cell types, including neurons. IL-1RAcPb is an isoform of IL-1RAcP expressed specifically in neurons and promotes their survival during acute inflammation. Here, we investigated in vivo whether IL-1RAcPb also promotes neuronal survival in a model of excitotoxicity. Intrastriatal injection of kainic acid (KA) in mice caused a strong induction of IL-1 cytokines mRNA in the brain. The stress response of cortical neurons at 12 h post-injection, as measured by expression of Atf3, FoxO3a, and Bdnf mRNAs, was similar in WT and AcPb-deficient mice. Importantly however, a delayed upregulation in the transcription of calpastatin was significantly higher in WT than in AcPb-deficient mice. Finally, although absence of AcPb signaling had no effect on damage to neurons in the cortex at early time points, it significantly impaired their long-term survival. These data suggest that in a context of excitotoxicity, stimulation of IL-1RAcPb signaling may promote the activity of a key neuroprotective mechanism.
    Frontiers in Cellular Neuroscience 01/2013; 7:9. · 4.47 Impact Factor

Publication Stats

11k Citations
1,158.35 Total Impact Points


  • 1989–2014
    • Laval University
      • • Département de Médecine Moléculaire
      • • Faculté de Médecine
      Québec, Quebec, Canada
  • 2013
    • Centre Hospitalier Universitaire de Québec (CHUQ)
      Québec, Quebec, Canada
    • CHU de Québec
      Québec, Quebec, Canada
  • 2007–2012
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2003–2012
    • The University of Calgary
      • Department of Clinical Neurosciences
      Calgary, Alberta, Canada
  • 1993–2012
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 2010
    • University of São Paulo
      • Department of Biochemistry (IQ)
      São Paulo, Estado de Sao Paulo, Brazil
  • 2008
    • Lund University
      • Department of Experimental Medical Science
      Lund, Skane, Sweden
  • 2001–2004
    • McGill University
      • Centre for Research in Neuroscience
      Montréal, Quebec, Canada
  • 1997–2003
    • Université du Québec
      Québec, Quebec, Canada
    • University of Pavia
      • Department of Public Health, Neuroscience, Experimental and Forensic Medicine
      Ticinum, Lombardy, Italy
  • 1999
    • McMaster University
      • Department of Psychiatry and Behavioural Neurosciences
      Hamilton, Ontario, Canada
  • 1998
    • University at Buffalo, The State University of New York
      • Department of Psychology
      Buffalo, NY, United States
  • 1995
    • Centre de Recherche Industrielle Québec
      Québec, Quebec, Canada
  • 1991–1994
    • Salk Institute
      • Clayton Foundation Laboratories for Peptide Biology
      La Jolla, CA, United States