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

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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.
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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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    • "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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