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GXK: monophosphoryl lipid A vaccination potential for Alzheimer's Disease

(Haven't seen this posted yet and this looks quite promising so would like to hear from some of the board members who are much more expert than myself. I've also attached a comment from noted neuroscientist Paul Patterson at CalTech)

Major Step Toward an Alzheimer's Vaccine

http://www.sciencedaily.com/releases/2013/01/130115143852.htm

"One of the main characteristics of Alzheimer's disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system's defenders, are unable to eliminate this substance, which forms deposits called senile plaques.

The team led by Dr. Serge Rivest, professor at Université Laval's Faculty of Medicine and researcher at the CHU de Québec research center, identified a molecule that stimulates the activity of the brain's immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant by GSK for many years, and its safety is well established.

In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice's ability to learn new tasks showed significant improvement in cognitive function over the same period.

The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer's disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. "The vaccine could be given to people who already have the disease to stimulate their natural immunity," said Serge Rivest. "It could also be administered as a preventive measure to people with risk factors for Alzheimer's disease."
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Dr. Patterson's comment:

"There are many indications of a subclinical, inflammatory state in AD. Whether this is a cause or effect of Aß accumulation is a topic of considerable interest. A number of epidemiological studies found that a history of use of anti-inflammatory medications can significantly postpone the onset of AD. Clinical trials of such drugs have provided some evidence of very modest, positive effects on AD progression. In mouse models, induction of proinflammatory cytokines can reduce Aß levels, while reducing cytokine efficacy can increase Aß. Moreover, stimulation of Toll-like receptors (TLRs) on microglia accelerates Aß removal in culture and in vivo, while knocking out TLR4 exacerbates Aß accumulation. A worry is that sustained activation of microglia, as with repeated injection of lipopolysaccharide (LPS) in mouse models, appears to result in excessive inflammation and increased Aß levels. Thus, it would be useful to have a molecule that hits the sweet spot of decreasing Aß while being safe. This new paper from Serge Rivest’s group at Laval University in Quebec describes results with a molecule that may indeed fulfill these criteria. Monophosphoryl lipid A (MPL) is a modified version of LPS that is a TLR4 agonist with immunomodulatory properties, but is much less toxic than LPS. Moreover, MPL has been used as an adjuvant in a number of vaccines without apparent side effects, and is deemed safe in humans, at least for acute applications.
Michaud et al. provide convincing evidence that MPL stimulates microglial phagocytosis of Aß in vitro and monocyte phagocytosis of Aß in mice. The MPL stimulation of the immune system is considerably milder than that seen with LPS. Most importantly, weekly i.p. injections of MPL over a period of three months in APPswe/PS1 AD mice results in significant (P <.01) decreases in plaque number and area in the cortex. Levels of extracellular Aß monomers are also down in the brain, and the number of Aß-containing microglia is strongly increased. The final key piece of evidence in such experiments is an analysis of learning and memory in the mouse model. Michaud et al. evaluated reversal learning in the T water maze and report that MPL treatment improves scores at a significance level of P <.05, although the scores of half of the controls overlap completely with those of the MPL mice. It will be informative to see the results of further behavioral analysis of these mice. Overall, then, peripheral injection of MPL lowers Aß and plaque levels in AD mice, and may positively affect learning. The mechanism of its action could be via the peripheral sink action of lowering blood levels of Aß and/or its stimulation of Aß uptake by brain microglia. Since this molecule is approved for human use in vaccines, MPL is a good candidate for clinical testing in AD."

http://www.alzforum.org/pap/annotation.asp?powID=142104

Comments and opinions?

AJ