Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 5, Pages 1941-1946Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1215165110
Keywords
innate immunity; microglial cells; monocytes; phagocytosis; inflammation
Categories
Funding
- GlaxoSmithKline Vaccines
- Canadian Institutes in Health Research (CIHR)
- Natural Sciences and Engineering Research Council
- Bourse de Recherche en Milieu Pratique Innovation (Fonds Quebecois de la Recherche sur la Nature et les Technologies-Conseil de Recherches en Sciences Naturelles et en Genie)
- CIHR
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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 beta (A beta) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to A beta accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear A beta 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 A beta 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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