title: Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology.
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.
authors: Neuroscience Laboratory, Department of Molecular Medicine, Centre Hospitalier Universitaire de Québec Research Center,  Laval University, Québec City, QC,  Canada G1V 4G2.
authors: Jean-Philippe
authors: JP
authors: Michaud
authors: Maxime
authors: M
authors: Hallé
authors: Antoine
authors: A
authors: Lampron
authors: Peter
authors: P
authors: Thériault
authors: Paul
authors: P
authors: Préfontaine
authors: Mohammed
authors: M
authors: Filali
authors: Pascale
authors: P
authors: Tribout-Jover
authors: Anne-Marie
authors: AM
authors: Lanteigne
authors: Rachel
authors: R
authors: Jodoin
authors: Christopher
authors: C
authors: Cluff
authors: Vincent
authors: V
authors: Brichard
authors: Rémi
authors: R
authors: Palmantier
authors: Anthony
authors: A
authors: Pilorget
authors: Daniel
authors: D
authors: Larocque
authors: Serge
authors: S
authors: Rivest
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008024:Ligands; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010587:Phagocytosis / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D008024:Ligands; D008050:Lipid A; D008070:Lipopolysaccharides; D053764:Presenilin-1; D051197:Toll-Like Receptor 4; C048436:monophosphoryl lipid A