Longevity Briefs: What Can Down Syndrome Patients Can Teach Us About Alzheimer’s Prevention?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Almost all Down syndrome sufferers will begin to accumulate amyloid β plaques (one of the hallmarks of Alzheimer’s disease) in their brains, decades before other people. This happens because the gene that encodes amyloid precursor protein (APP, the precursor to amyloid β) is found on chromosome 21, the chromosome that Down syndrome patients possess an extra copy of. This extra copy also affects inflammation, which can accelerate cognitive decline.

Despite this predisposition to earlier Alzheimer’s onset, some people with Down syndrome are unusually resistant to cognitive decline, even though they develop the typical Alzheimer’s pathology, like the accumulation of amyloid β and Tau tangles. In this study, researchers investigate why that might be, and whether the answer could lead to better Alzheimer’s treatments.

The discovery:

Researchers suspected that the resilience of some Down syndrome patients might be explained by mutations in their microglia – resident white cells of the brain that clear up debris and regulate inflammation. Down syndrome is associated with increased mutation rates in haematopoietic cells – the cell that give rise to red and white blood cells. To test this possibility, researchers identified a gene variant that sometimes occurs as a result of mutation in blood cells and is common in Down syndrome patients who resist Alzheimer’s: CSF2RB A455D. This gene variant encodes part of a receptor for an immune signalling molecule that promotes cell survival. They then deliberately introduced this mutation into microglial cells from healthy individuals and from Down syndrome patients, and then injected those microglia into 4-10 month-old mice.

The researchers found that regardless of whether the microglia originated from Down syndrome patients or not, microglia carrying the CSF2RB variant had improved phagocytosis (the ability to absorb and break down waste), were resistant to becoming senescent (a state in which cell division is permanently halted) and suppressed inflammation in response to Tau protein when compared to unmodified microglia. Furthermore, while introduction of Tau protein into the brains of mice overwhelmed their native microglia and caused them to become diseased, the new modified microglia quickly replaced those diseased microglia after Tau exposure.

The implications:

Microglia appear to be key players in preventing neurodegenerative disease and preserving brain function. However, in old age these cells are overwhelmed and become dysfunctional. This research suggests that there is potential for one day using modified microglia (or otherwise enhancing microglial activity) to help combat neurodegenerative disease in both Down syndrome and otherwise healthy people. It’s also an interesting example of how studying those who are at particular risk of a disease, then looking for exceptions to the rule, can give us clues about how to prevent it.

There is some evidence that healthy lifestyle factors like physical exercise, good quality sleep, plant-rich diets and calorie restriction can enhance microglial function.