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New target identified to prevent age-related diseases

Cognitive degeneration is one of the most debilitating features of aging, and considerable research goes into understanding what makes brain cells healthy and why they lose function as people age. Diseases, such as Alzheimer’s, along with traumatic brain injuries, can also cause cognitive decline. A new study by scientists from the Trinity Biomedical Sciences Institute (TBSI) has now shed new light on the role of specialized microglial cells in this process.

Microglia are specialized immune cells that are found in the tissues of the nervous system, particularly the brain and spinal cord. Usually, they function to support nerve cells, defend against invading microbes, clear debris and remove dying nerve cells by engulfing and digesting them. They are thus critical to the functioning of healthy brain cells. 

However, emerging research indicates that microglia can function differently depending on molecular and biochemical changes occurring within these specialized cells; indeed, once activated by pathological stimuli, microglia can alter their functional states to either contribute to or mitigate disease progression. In this light, they may cause effects that worsen a patient’s condition.

In the current study, published in the leading international journal, Science Advances, the researchers investigated changes that take place in the microglia in the brains of aging mice and mice that have had traumatic brain injuries. In particular, they considered the presence of autofluorescent microglia and found that this type of cell was more common in aged mice and in mice that had suffered a brain injury. 

Autofluorescence is the tendency of cells to emit light of one color after they have absorbed light of another, and it occurs because specific substances inside the cells absorb light. Because the microglia are the garbage collectors of the brain, they gradually accumulate substances that come from the cells and debris they engulf and absorb. These substances include fat molecules, cholesterol crystals, metals and misfolded proteins. 

The researchers found that, compared with young mice, one-third of the microglia in the brains of old mice exhibited autofluorescence. These cells were also characterized by profound changes in lipid and iron content, in oxidative stress levels, and in their ability to move around and engulf pathogens and dead cells. 

“As the brain ages, these materials build up inside autofluorescent microglia, which increase their autofluorescence as a result. Unfortunately, this accumulation of cellular debris also makes it harder for the microglia to perform their essential garbage collection tasks in the brain and to prevent neurological injury and neurodegenerative disease.,” said study lead author Professor David Loane.

“In this study we found – in aged animals – that these microglia adopt a unique, dysfunctional state, which has a number of problematic impacts. For example, there is an increase in cellular stress and damage, an accumulation of fats and iron, alterations to metabolic processes and an increase in production of molecules that over-egg the immune response.” 

In addition, the scientists demonstrated that autofluorescent microglia were associated with increased levels of inflammation, and that both of these factors were more pronounced under pathological conditions, such as in the progression of Alzheimer’s disease. Encouragingly, the effects were reversed when the researchers used medications to remove and replace the autofluorescent microglia in the brains of aged mice. This may give hope that these cells could be targeted in treatments in future.

Mice that had suffered brain injuries still showed increased presence of autofluorescent microglial cells a year after the injury. “Furthermore, environmental exposure to acute traumatic brain injury in animals accelerated the age of onset and tissue-wide distribution of autofluorescent microglia by increasing oxidative stress damage in the brain of injured animals,” said Professor Loane.

“As a result, increasing evidence now suggests that the accumulation of autofluorescent microglia contributes to diseases of ageing and neurodegeneration. If these sub-populations of microglia are highly inflammatory and damaging to the brain, then targeting them could be a new strategy for treating aging-related diseases.”

By Alison Bosman, Staff Writer

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