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

TitleToll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology.
Publication TypeJournal Article
Year of Publication2013
AuteursMichaud, J-P, Hallé, M, Lampron, A, Thériault, P, Préfontaine, P, Filali, M, Tribout-Jover, P, Lanteigne, A-M, Jodoin, R, Cluff, C, Brichard, V, Palmantier, R, Pilorget, A, Larocque, D, Rivest, S
JournalProc Natl Acad Sci U S A
Volume110
Issue5
Pagination1941-6
Date Published2013 Jan 29
ISSN1091-6490
KeywordsAlzheimer Disease, Amyloid beta-Protein Precursor, Animals, Blotting, Western, Brain, Cell Line, Cytokines, Gene Expression, HEK293 Cells, Humans, Immunity, Innate, Ligands, Lipid A, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Microscopy, Fluorescence, Phagocytosis, Presenilin-1, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptor 4
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.

DOI10.1073/pnas.1215165110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23322736
PubMed Central IDPMC3562771
Grant List / / Canadian Institutes of Health Research / Canada