Provoking Innate Immune Clearance of Protein Aggregates Improves Cognition in a Squirrel Monkey Model of Alzheimer's Disease
A novel pulsed approach to immunotherapy targeting Alzheimer's disease has been shown to reduce both amyloid-β and tau aggregates in old squirrel monkeys, as well as improve cognitive function. This species offers a potentially less problematic and artificial animal model for the condition, in that aged squirrel monkeys naturally develop amyloid-β aggregates, unlike mice which must be engineered into exhibiting specific features of Alzheimer's pathology. Thus it is hoped that cognitive improvements following therapy in this species will be more likely to also occur in human patients.
Researchers have demonstrated that elderly monkeys had up to 59 percent fewer plaque deposits in their brains after treatment with CpG oligodeoxynucleotides (CpG ODN), compared with untreated animals. These amyloid beta plaques are protein fragments that clump together and clog the junctions between neurons. Brains of treated animals also had a drop in levels of toxic tau. This nerve fiber protein can destroy neighboring tissue when disease-related changes to its chemical structure cause it to catch on other cells.
The investigators say the treatment led to cognitive benefits as well. When presented with a series of puzzles, elderly monkeys given the drug performed similarly to young adult animals and much better than those in their age group that had remained untreated. The treated monkeys also learned new puzzle-solving skills faster than their untreated peers. According to researchers, past treatment efforts targeting the immune system failed because the drugs overstimulated the system, causing dangerous levels of inflammation, which can kill brain cells. "Our new treatment avoids the pitfalls of earlier attempts because it is delivered in cycles, giving the immune system a chance to rest between doses."
A growing body of evidence has implicated the immune system, the set of cells and proteins that defend the body from invading bacteria and viruses, as a contributor to Alzheimer's disease. A subset of immune cells, those within the innate immune system, swallow and clear away debris and toxins from bodily tissues along with invading microbes. Studies have shown that these immune custodians become sluggish as a person ages and fail to clear toxins that cause neurodegeneration.
The new investigation is the first to target the innate immune system with a potential therapy for the disorder in monkeys. The CpG ODN drugs are part of a class of innate immune regulators that quicken these worn out immune custodians. The research team is also the first to use the "pulsing" drug administration technique to avoid excess inflammation, the immune-driven responses like swelling and pain that result from the homing in by immune cells on sites of injury or infection. While necessary to immune defenses and healing, too much inflammation contributes to many disease mechanisms.
Interesting that they maintain a balance between innate immune stimulation and inflammation. I wonder if an existing immunologic adjuvant would have a similar effect?