The Use of Adjuvants in Alzheimer's Treatment

Here is an interesting approach to fighting Alzheimer's disease: use adjuvants to activate microglia in the nasal cavity.

Frenkel et al. publishing the Annals of Neurology show that the administration of an adjuvant called Protollin into the nasal cavity of both young and old mice transgenically engineered to get Alzheimer's disease can reduce the plaque burden and improve the disease.

There has been a lot of interest in using the immune system to help treat Alzheimer's disease, but the technique has some major and perhaps insurmountable risks. I talked before about how Alzheimer's is a disease of molecular crud. A protein called ABeta which is derived from a protein in your body called APP forms aggregates -- called plaques -- and progressively kills neurons. One technique that has been tried to fight this is to immunize individuals against the protein ABeta. The idea is that the immune system will then go around and consume the plaques.

This idea worked great in mice; it caused substantial improvement in the disease. However when it was tried in humans a substantial number developed serious brain inflammation that in some cases lead to death. Not good. So the field of Alzheimer's vaccines is a bit touchy. You really would like to activate the immune system in a way that won't cause encephalitis.

Enter Frenkel et al. The authors use an adjuvant to activate microglia in the periphery. An adjuvant is a compound that is often administered with a vaccine to facilitate the appropriate immune response. In most cases adjuvants are made of a bacterial constituent called lipopolysaccharide. You can think of an adjuvant as an immune activator. The particular type of immune response depends on the adjuvant. The primary immune cell in the central nervous system is called a microglia. It is a lot like a macrophage. It just hangs out into the CNS until something goes wrong.

Frenkel et al. show that if you administer the adjuvant Protollin into the nasal cavity, you can activate microglia in the brain. This actually makes a lot of sense. The nasal cavity is one of the easiest access points to the CNS. There is a part of the skull that is filled with little holes called the cribiform plate. Through these holes run neurons that are attached to the olfactory neurons in your nose that allow for the sense of smell. Given the close proximity of the olfactory neurons to the CNS, it wouldn't be unreasonable if a compound administered here would have access to microglia.

The authors administered protollin to both young and adult rats. In some cases, they also used an additional drug called glatiramer acetate (GA). GA is used to shift the immune response from a pro-inflammatory response to a inflammation suppressing response. (From shift from Th1 T-cells to Th2 T-cells, but that is sort of technical.)

Anyway, after administering the drug to young rats intranasally once a week for 8 weeks, the authors looked at endpoints to measure the progression of the disease. (As an aside, remember that these are transgenic mice engineered to get accumulations of ABeta. Mice do not naturally get Alzheimer's.) The end points were stuff like concentration of soluble and insoluble ABeta. (ABeta comes in two forms AB40 and AB42, but the difference between the two isn't that important in this case.) They also stained for plaques and activated microglia in the mice brains.

Here is the data for the young mice. (Figure 1 from the paper)

The top part of the figure is staining for the plaques -- shown in green. The bottom parts shows measurements of various forms of ABeta. You can see how the Protollin administration substantially reduced both the plaques and the ABeta in these animals.

That is fine and good but Alzheimer's is not particularly a problem in the young, and generally it is not prophylatically treated for substantially portions of the person's lifetime. What would be the result if an older animal with advanced disease were treated.

These results are shown below. (Figure 2 from the paper.)

The top part again shows staining for plaques in green. The bottom part again shows measurements of various forms of ABeta. Again protollin administration substantially reduced ABeta in these animals. However, in this case, the authors did not find a significant reduction in plaque burden (see fibril burden or panel C).

The authors go on to stain for microglia. They show that the nasal administration of Protollin does indeed lead to activated microglia in the CNS. Interestingly in the young animals, this activation disappears once the plaques have been removed -- a good sign if you want to use this as a treatment strategy because it means the inflammation is self-limiting.

This is interesting work because it might solve some of the problems associated with brain inflammation and Alzheimer's vaccines. We know that vaccines have promise. The trick is to manipulate the immune system to cause a disease-modifying response without total brain inflammation. If selective use of adjuvants like Protollin will help this happen, then I think this is a very promising line of research.

The authors summarize the significance of their work:

We also tested nasal Protollin given weekly for 6 weeks in 24-month-old APP Tg mice to test its effect in animals with a large amyloid burden. We found a reduction in both soluble and insoluble forms of ABeta (both 1-40 and 1-42), though there was no significant reduction in fibrillar A as measured by thioflavin-S. These results are consistent with our previous studies in which only GA plus Protollin was effective in clearing fibrillar A in older animals, whereas Protollin alone reduced total A. We also found improved cognition in 24-month-old animals treated with Protollin alone as measured by fear conditioning. Although our results do not suggest that Protollin acts directly in the brain, direct hippocampal injection demonstrated similar effects to what we observed in the cervical lymph node after nasal Protollin. Specifically, intrahippocampal injection was associated with the upregulation of the antiinflammatory cytokine IL-10, downregulation of the proinflammatory cytokines IL-12 and IL-23, upregulation of IDE, and upregulation of TLR-2 and TLR-4.

In summary, we demonstrate that nasal Protollin activates microglia/macrophage cells to clear amyloid without induction of an inflammatory signal that could lead to neurotoxicity, and when young animals are treated in a prevention paradigm, there is no residual microglial activation once the amyloid is cleared. Furthermore, nasal Protollin decreases astrocytosis in animals with a large amyloid burden. Despite the fact that we did not observe toxicity in animals given Protollin, we caution that long-term administration of Protollin in humans with AD might cause side effects that we did not observe in our animal studies. Nonetheless, because we found a reduction of A without apparent toxicity when given weekly for 8 months and single doses of Protollin have been given to people without toxicity, we speculate that Protollin may be beneficial for both the prevention and treatment of AD.

The emphasize a point that I think it is important to repeat. Many things work in animals that do not work in humans. Though this research is promising, it is still certainly possible that treatments like this would also cause encephalitis in humans. This adjuvant has been used in humans before with limited negative side-effects, but that is something we need to check before pushing it any further.

Hat-tip: Faculty of 1000

Frenkel, D., Puckett, L., Petrovic, S., Xia, W., Chen, G., Vega, J., Dembinsky-Vaknin, A., Shen, J., Plante, M., Burt, D.S., Weiner, H.L. (2008). A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Annals of Neurology, 63(5), 591-601. DOI: 10.1002/ana.21340