There are many indications of a subclinical, inflammatory state in AD. Whether this is a cause or effect of Aβ 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 Aβ levels, while reducing cytokine efficacy can increase Aβ. Moreover, stimulation of Toll-like receptors (TLRs) on microglia accelerates Aβ removal in culture and in vivo, while knocking out TLR4 exacerbates Aβ 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 Aβ levels. Thus, it would be useful to have a molecule that hits the sweet spot of decreasing Aβ while being safe. This new paper from Serge Rivest’s group at Laval University in Quebec describes results with a...  Read more

There are many indications of a subclinical, inflammatory state in AD. Whether this is a cause or effect of Aβ 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 Aβ levels, while reducing cytokine efficacy can increase Aβ. Moreover, stimulation of Toll-like receptors (TLRs) on microglia accelerates Aβ removal in culture and in vivo, while knocking out TLR4 exacerbates Aβ 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 Aβ levels. Thus, it would be useful to have a molecule that hits the sweet spot of decreasing Aβ 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 Aβ in vitro and monocyte phagocytosis of Aβ 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 Aβ monomers are also down in the brain, and the number of Aβ-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 Aβ 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 Aβ and/or its stimulation of Aβ uptake by brain microglia. Since this molecule is approved for human use in vaccines, MPL is a good candidate for clinical testing in AD.

View all comments by Paul Patterson

The recent paper by Rivest and colleagues reports that a modified form of the Toll-like receptor 4 ligand monophosphoryl lipid A (MPL) elicits improvement in cognitive ability and reduction in plaque burden in APP/ΔE9PS1 mice. This study is of particular interest, given the literature documenting the varied effects of lipopolysaccharide (LPS) in murine models of AD. MPL is a recently FDA-approved adjuvant comprising a mixture of lipid A species that have been chemically modified, altering signaling characteristics through TLR4. MPL stimulates a much less robust proinflammatory response than LPS, while maintaining the induction of chemotaxis and phagocytosis in monocytes and microglia. Indeed, Michaud et al. document that MPL activates a modest inflammatory response both in vitro and in vivo, but effectively enhances microglia and monocyte phagocytosis of amyloid-β (Aβ).

The key experiment is shown in Figure 6, in which they systemically administer MPL weekly for three months to three-month-old APP/ΔE9PS1 mice. These mice first exhibit plaque deposition at about six months of...  Read more

The recent paper by Rivest and colleagues reports that a modified form of the Toll-like receptor 4 ligand monophosphoryl lipid A (MPL) elicits improvement in cognitive ability and reduction in plaque burden in APP/ΔE9PS1 mice. This study is of particular interest, given the literature documenting the varied effects of lipopolysaccharide (LPS) in murine models of AD. MPL is a recently FDA-approved adjuvant comprising a mixture of lipid A species that have been chemically modified, altering signaling characteristics through TLR4. MPL stimulates a much less robust proinflammatory response than LPS, while maintaining the induction of chemotaxis and phagocytosis in monocytes and microglia. Indeed, Michaud et al. document that MPL activates a modest inflammatory response both in vitro and in vivo, but effectively enhances microglia and monocyte phagocytosis of amyloid-β (Aβ).

The key experiment is shown in Figure 6, in which they systemically administer MPL weekly for three months to three-month-old APP/ΔE9PS1 mice. These mice first exhibit plaque deposition at about six months of age. Michaud et al. report that there is an approximate 50 percent reduction in plaque burden in MPL-treated mice. In contrast, mice that were treated weekly with LPS had increased plaque burden. In a separate analysis of older mice (10 months old) they report about a fourfold increase in Aβ-containing microglia after five consecutive daily treatments with MPL. These data are consistent with an MPL-stimulated phagocytic clearance of amyloid deposits. The basis for the loss of soluble Aβ species is unexplained.

They report improved behavior in a T maze, but it is difficult to interpret these data given that the control mice fall into distinct groups of roughly equal size that exhibit dramatically different behavior. One subset of mice in the control group appears to be no different from the MPL-treated mice, while another subset requires more than 20 trials to reach criterion. It seems as though the statistical effect of improvement in this cognitive task following MPL-treatment is achieved only by inclusion of this severely compromised subset of mice.

Two important issues are that it is not clear whether MPL is blood-brain barrier penetrant, and whether its effects in the brain are direct or indirect. The study is an interesting addition to the literature of TLR4 action in the brain and provides a new tool to dissect TLR involvement in AD and other CNS disease models.

View all comments by Gary Landreth