Tired Immune Cells in the Brain May Cause Alzheimer’s

A recent study published in “Immunology,” a medical journal specializing in immunology, discovered that ‘exhausted’ immune cells in the brain can potentially cause Alzheimer’s disease.

“As Alzheimer’s disease develops, it affects both mice and humans, causing the brain’s immune cells, known as the microglia, to wither. The key genetic variant associated with Alzheimer’s disease, namely, ‘APOE4’, can mediate these effects,”

The research team has named this new type of ‘exhausted’ cells ‘TIM (terminally inflammatory microglia)’. TIM has lost its ability to efficiently remove plaques in the brain, thus potentially leading to Alzheimer’s disease.

The team also revealed how the anti- Alzheimer’s disease drug ‘aducanumab’ can interact with the brain’s immune cells. They further showed that when mice with the APOE4 mutation are treated with aducanumab, TIM regains some of its functions.

Human bodies have one of three APOE gene variants: APOE2, APOE3, and APOE4. The APOE4 gene negatively impacts blood circulation in the blood vessels, thus thwarting their proper functioning. When blood vessels that deliver nutrients and oxygen and remove waste, fail to perform these functions, the risk of dementia increases. Therefore, the APOE4 variant, which is passed on to about 20% of the population, is considered one of the greatest genetic risk factors for Alzheimer’s.

After developing a mouse model of Alzheimer’s disease that expresses human APOE variants, the research team caused the mice’s bodies to age to understand how APOE4 impacts their brains while Alzheimer’s Disease develops in the brains. They created a single-cell map of the brain’s immune cells in the mice which led to the discovery of a group of microglia filled with signs of stress and inflammation that had not been previously described. While other variants had relatively fewer TIMs, the brains of mice with APOE4 were overrun with TIM.

These findings suggest that APOE4 may increase the risk of Alzheimer’s by damaging the brain’s immune cells.

The researchers also found that treating the mice with the recently approved Alzheimer’s drug, aducanumab, improved their condition and rehabilitated the damaged TIM. The effect of this drug was more visible in mice with APOE4.

“Restoring microglia from a state of being too exhausted to function can give the brain the strength it needs to protect itself. If so, TIM could be a promising therapeutic target. If we can revert them to a healthy state, perhaps the immune system can suppress Alzheimer’s,”

The research team now aims to develop drugs that can interfere with this process, maintain the health of microglia, and contribute to reducing cognitive decline by exploring signal molecules that lead to the formation of TIM. In the long term, this could lead to a new Alzheimer’s treatment.

Although TIM may not have received much attention so far, the research team suspects that these exhausted immune cells could be involved in other brain diseases, from tumors to Parkinson’s disease. Since inflammation accumulates TIM, what we are seeing may not be limited to Alzheimer’s.

However, the research team noted that the statistical power was limited because a single library was generated for each genotype and age, stating, “Our analysis of the human dataset confirmed a strong correlation between TIM frequency and gender, but there was insufficient power in mice. Verification of these results will require future work.”

By. Ji Yeon Kim