Treatment with Lipopolysaccharide Derivative Shows Promise in Alzheimer's Disease Mouse Model

Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria. Intact bacterial lipopolysaccharides are macromolecules of molecular mass 10–20 kDa made up of three structural components: a hydrophobic lipid section, lipid A, which is responsible for the toxic properties of the molecule; a hydrophilic core polysaccharide chain; and a repeating hydrophilic O-antigenic oligosaccharide side chain that is specific to the bacterial serotype. LPS is a heat stable endotoxin and has been recognized as a key factor in septic shock in humans and, more generally, in inducing a strong immune response in normal mammalian cells. The lipid A moiety has been identified as critical to the endotoxin activity of LPS. Although several lipid A species, including LPS and synthetic analogs, have been developed and tested as therapeutic agents for the treatment of cancer, only 3-O-desacyl-4'-monophosphoryl lipid A (MPL) has been evaluated as a cancer vaccine adjuvant in published human clinical trials. MPL—a Toll-like receptor 4 agonist —comprises the lipid A portion of Salmonella minnesota LPS from which the (R)-3-hydroxytetradecanoyl group and the 1-phosphate have been removed by successive acid and base hydrolysis. LPS and MPL induce similar cytokine profiles, but MPL is at least 100-fold less toxic.

Investigators at the Laval University (Quebec, Canada) worked with the APPswe/PS1 mouse model of human Alzheimer's disease. They reported in the January 15, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America that repeated systemic injections of MPL, but not LPS, over a twelve-week period significantly improved Alzheimer's disease-related pathology in APPswe/PS1 mice. MPL treatment led to an 80% reduction in amyloid-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.

"The [MPL] vaccine could be given to people who already have the disease to stimulate their natural immunity," said senior author Dr. Serge Rivest, professor of neurosciences at Laval University. "It could also be administered as a preventive measure to people with risk factors for Alzheimer's disease. When our team started working on Alzheimer's disease a decade ago, our goal was to develop better treatment for Alzheimer's patients. With the discovery announced today, I think we are close to our objective."


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