Boosted Microglial Function as an Alzheimer's Therapy

The immune system is a very efficient mechanism for certain types of task, if it can just be harnessed and put to work. Left to its own devices throughout most of a life span it can effectively destroy misbehaving cells, remove some types of harmful protein aggregates, and of course defend against self-replicating invaders of many different types. There is more besides, but if you want some biological line item in the body destroyed, then you could do worse than trying to use the immune system as your tool. Given this, it shouldn't be surprising to see that this dawning age of cell biology involves numerous efforts to produce immune therapies: ways to enhance and direct the immune system's actions to treat medical conditions. In the case of Alzheimer's disease immunotherapies gaining the most press in recent years have been those that aim to directly remove the amyloid beta deposits characteristic of the disease. There are a variety of ways in which that can goal might be achieved, such as through the use of a designed compound that is targeted by immune cells and happens to bind to amyloid beta, or by altering immune cells so that they target amyloid directly. The immune system is built around acquisition and management of recognition of protein fragments, so this sort of approach plays to its strengths.

There are other approaches, however. Microglia are specialized immune cells of the central nervous system and are already capable of attacking and removing amyloid beta. Like the rest of the immune system, their activity diminishes with age, however. There are groups working on the foundations of treatments based on the transplant of young microglia into old brains, a potential methodology that is becoming increasingly attractive given recent discoveries about aging and stem cells. Delivering young stem cells into old tissue can have the effect of reversing some of the responses to aging in native stem cells, restoring them to more youthful levels of activity as the environment of signals and proteins levels is temporarily shifted. Will this raise cancer risk due to more cellular activity in a damaged environment, and can that risk be well managed, as it has been in the cell therapy field to date? Time will tell, but I expect so.

Along these lines, the researchers quoted below are working on a way to skip the cell transplants and jump straight to the renewed cellular activity part of the treatment. Ultimately I expect much of the cell therapy field to evolve to use this sort of technique, in which the bulk of the work is direct manipulation or reprogramming of native cells, often by altering the levels of specific proteins present in the tissue environment. Currently such efforts are comparatively crude, but they will improve rapidly in years to come as cell biology becomes less of a jungle and more of a well-mapped city:

Targeted immune booster removes toxic proteins in mouse model of Alzheimer's disease

Using dementia-prone mice, the team gave monthly injections of an immune system booster known as a type B, CpG, oligodeoxynucleotide that specifically binds to Toll-like receptor 9, or TLR9 for short. Activation of TLR9 triggers an immune response. Tests in mice that received the immune system booster injections showed that amyloid plaque formation was 50 percent to 70 percent less than in mice that received no therapy. Reductions in amyloid beta were almost the same for mice treated early on, at age 7 months, and before disease onset, compared to mice treated at age 11 months, which already had mild dementia. Immunostaining tests on brain tissue in treated mice showed one to two times fewer damaged neurons containing disease-related tau aggregates than in untreated mice.

According to researchers, treated mice behaved "almost like normal" mice that never develop Alzheimer's-like symptoms. Unlike vaccines, which try to trigger an antibody-mediated stimulation of the body's immune system, [the] team's new approach attempts to "jump start and rejuvenate" the brain's natural microglial cell repair function. The breakdown of microglial repair - possibly from aging - has been linked for decades to the formation and removal of amyloid plaques and tau tangles in Alzheimer's disease.

Researchers say they selected TLR9 as the immune booster because it was a known stimulant for removing germs. A bacterial cytosine-guanosine sequence, or CpG, such as type B, CpG, oligodeoxynucleotide, was chosen to help activate TLR9 on brain cells because previous testing had shown it to be effective at triggering an immune response in both mice and humans, with very few side effects. "Now that we have shown that we can influence microglial function in Alzheimer's disease, to both prevent and repair tau-damaged brain tissue, then it is highly plausible that our treatment approach could also be applied to other neurodegenerative diseases tied to aging."

Amyloid beta and Tau Alzheimer's Disease Related Pathology is reduced by Toll-like Receptor 9 Stimulation

We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. In the present study, we used the 3xTg-AD mice with both Aβ and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aβ and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice.
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