[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2015; DOI:10.1038/npp.2015.279 · 7.05 Impact Factor
[Show abstract][Hide abstract] 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.
Alzheimer's Research and Therapy 04/2015; 7(1). DOI:10.1186/s13195-015-0125-2 · 3.98 Impact Factor
[Show abstract][Hide abstract] 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.
Cell Research 03/2015; 25(5). DOI:10.1038/cr.2015.37 · 12.41 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Journal of Interferon & Cytokine Research 08/2014; 34(8):615-22. DOI:10.1089/jir.2014.0019 · 2.00 Impact Factor
[Show abstract][Hide abstract] 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; 34(7). DOI:10.1038/jcbfm.2014.80 · 5.41 Impact Factor
[Show abstract][Hide abstract] 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; 220(3). DOI:10.1007/s00429-014-0759-z · 5.62 Impact Factor
[Show abstract][Hide abstract] 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 04/2014; 15(4):6453-74. DOI:10.3390/ijms15046453 · 2.86 Impact Factor
[Show abstract][Hide abstract] 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 03/2014; 5:136. DOI:10.3389/fimmu.2014.00136
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an anti-tumor necrosis factor alpha (TNF-α) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85 × 104 plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 μg/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P = 0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P < 0.01) or combined with ETA (P < 0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-α inhibitor, to improve prognosis of HSE.
Antiviral research 12/2013; 100(3):649–653. DOI:10.1016/j.antiviral.2013.10.007 · 3.94 Impact Factor