Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology

Neuroscience Laboratory, Department of Molecular Medicine, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada G1V 4G2.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2013; 110(5). DOI: 10.1073/pnas.1215165110
Source: PubMed


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.

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Available from: Peter Thériault, Oct 06, 2015
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    • "Microglia deficient in TLR2, TLR4, or the co-receptor CD14 are not activated by Ab and do not show a phagocytic response (Reed- Geaghan et al., 2009). Furthermore, stimulation of microglial cells with TLR2-, TLR4-, or TLR9-specific agonists accelerates Ab clearance both in vitro and in vivo (Michaud et al., 2013). It has been shown that the administration of the TLR9 agonist CpG oligonucleotides (ODN) containing unmethylated CpG sequences to AD model Tg2576 mice induced a reduction of cortical and vascular Ab levels, without apparent toxicity, and improved cognitive function, with a recent study in 3xTg mice showing the same approach also can reduce tau-related pathology in association with cognitive benefits (Scholtzova et al., 2009, 2014). "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6):1162-1176. DOI:10.1016/j.neuron.2014.12.064 · 15.05 Impact Factor
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    • "We and others have demonstrated that microglial activation associated with TLR9 has benefits in amyloid depositing mice [9,69]. A recent study using the TLR4 agonist monophosphoryl lipid A (MPL) gave further evidence that TLRs can be a therapeutic target in AD [42]. However, only limited studies have been performed in tau mouse models. "
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    ABSTRACT: Alzheimer¿s disease (AD) is the most common cause of dementia, and currently, there is no effective treatment. The major neuropathological lesions in AD are accumulation of amyloid ß (Aß) as amyloid plaques and congophilic amyloid angiopathy, as well as aggregated tau in the form of neurofibrillary tangles (NFTs). In addition, inflammation and microglia/macrophage function play an important role in AD pathogenesis. We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. We have previously shown in the Tg2576 AD model that CpG ODN can reduce amyloid deposition and prevent cognitive deficits. In the present study, we used the 3xTg-AD mice with both Aß and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aß and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice. Our data indicates that modulation of microglial function via TLR9 stimulation is effective at ameliorating all the cardinal AD related pathologies in an AD mouse model mice suggesting such an approach would have a greater chance of achieving clinical efficacy.
    09/2014; 2(1):101. DOI:10.1186/PREACCEPT-2151623761356337
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    • "The beneficial aspects of the immune response in the nervous system are beginning to be appreciated and their potential as pharmacologic targets in neurologic disease is being explored (Graber and Dhib-Jalbut, 2009). In a mouse model of Alzheimer’s disease, repeated systemic injections of monophosphoryl lipid A, a LPS-derived Toll-like receptor 4 (TLR4) agonist that exhibits immunomodulatory properties at non-pyrogenic doses induced a potent phagocytic response by microglia, reduced the amyloidβ load in the brain and enhanced cognitive function (Michaud et al., 2013). "
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    ABSTRACT: In healthy individuals, infections of the central nervous system (CNS) are comparatively rare. Based on the ability of microglial cells to phagocytose and kill pathogens and on clinical findings in immunocompromised patients with CNS infections, we hypothesize that an intact microglial function is crucial to protect the brain from infections. Phagocytosis of pathogens by microglial cells can be stimulated by agonists of receptors of the innate immune system. Enhancing this pathway to increase the resistance of the brain to infections entails the risk of inducing collateral damage to the nervous tissue. The diversity of microglial cells opens avenue to selectively stimulate sub-populations responsible for the defence against pathogens without stimulating sub-populations which are responsible for collateral damage to the nervous tissue. Palmitoylethanolamide (PEA), an endogenous lipid, increased phagocytosis of bacteria by microglial cells in vitro without a measurable proinflammatory effect. It was tested clinically apparently without severe side effects. Glatiramer acetate increased phagocytosis of latex beads by microglia and monocytes, and dimethyl fumarate enhanced elimination of human immunodeficiency virus from infected macrophages without inducing a release of proinflammatory compounds. Therefore, the discovery of compounds which stimulate the elimination of pathogens without collateral damage of neuronal structures appears an achievable goal. PEA and, with limitations, glatiramer acetate and dimethyl fumarate appear promising candidates.
    Frontiers in Cellular Neuroscience 05/2014; 8:138. DOI:10.3389/fncel.2014.00138 · 4.29 Impact Factor
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