By Chiamaka Egwu
Scientists have found that a protein associated with youth may help restore some functions of ageing brain immune cells, raising new possibilities for research into brain ageing and Alzheimer’s disease.
The study, conducted by researchers at the Icahn School of Medicine at Mount Sinai in the United States, found that restoring a protein known as TIMP2 improved the ability of ageing brain immune cells to clear cellular waste and reduced molecular signs associated with inflammation in mice.
Published in Nature Communications, the findings provide new insights into how proteins circulating in the body may influence the brain’s natural defence system as people grow older.
However, researchers cautioned that the results are based on animal experiments, and further studies are needed to determine whether the same effects can be achieved safely and effectively in humans.
How ageing affects the brain’s immune system
Ageing is a major risk factor for Alzheimer’s disease and other neurodegenerative conditions. Scientists are continuing to investigate the biological changes that make the brain more vulnerable to damage as people grow older.
One area of interest is the role of microglia, specialised immune cells that help maintain a healthy brain environment.
These cells act as the brain’s maintenance and defence system by removing cellular waste, responding to injury and helping regulate the environment surrounding neurons, the cells responsible for transmitting information.
As the brain ages, microglia can become less effective at performing these functions. They may also develop changes associated with inflammation and cellular stress, potentially disrupting the conditions needed for normal brain activity.
The new study identified TIMP2 as a protein that helps maintain healthy microglial function and may counter some of these age-related changes.
“TIMP2 facilitates healthy function for the brain’s immune cells,” said Joseph M. Castellano, associate professor of neuroscience at the Icahn School of Medicine at Mount Sinai and corresponding author of the study.
He explained that the protein supports the ability of microglia to clear cellular debris and limit potentially harmful responses that become more common with age.
Castellano added that the findings build on earlier research identifying TIMP2 as a regulator of synaptic plasticity through the extracellular matrix.
Synaptic plasticity is the brain’s ability to strengthen or weaken connections between neurons, a process essential for learning and memory. The extracellular matrix is a network of molecules surrounding cells that helps regulate their activity.
Removing TIMP2 triggers changes linked to ageing
To investigate the protein’s role, the researchers examined mice in which TIMP2 had been removed from the body or selectively eliminated from particular cell types, including microglia and neurons.
The team used several techniques to assess changes in brain cells, including single-nucleus RNA sequencing, detailed imaging, functional tests and a method known as _in vivo_ microdialysis, which measures substances in the fluid surrounding cells in living tissue.
The results showed that mice lacking TIMP2 developed changes in their microglia associated with ageing and brain injury.
The cells displayed altered activation markers, reduced capacity to remove cellular debris and molecular signatures linked to cellular senescence — a state associated with ageing and cellular stress.
Researchers also detected increased levels of proteins associated with inflammation and stress in the environment surrounding brain cells.
The findings suggest that TIMP2 helps prevent microglia from shifting towards states that may compromise their protective functions.
Restoring the protein improves cell function in older mice
The researchers next investigated whether restoring TIMP2 could counter some of the changes associated with ageing.
They administered the protein through injections to older mice, allowing it to circulate in the bloodstream.
Following treatment, the animals’ microglia showed improved ability to clear cellular debris and fewer molecular markers associated with inflammatory states.
The results indicate that restoring TIMP2 may help ageing brain immune cells recover some functions that typically deteriorate over time.
Rather than demonstrating that the brain itself had become young again, the findings point to improvements in specific cellular processes involved in maintaining brain health.
The study also suggests that proteins circulating in the bloodstream may influence the behaviour of microglia, offering researchers another avenue for investigating communication between the body and the ageing brain.
Implications for Alzheimer’s disease research
The findings could have implications for understanding Alzheimer’s disease and other conditions associated with age-related changes in the brain.
Microglia play an important role in maintaining the brain’s environment. When their normal functions become impaired, the resulting changes may contribute to conditions that are less supportive of healthy neuronal activity.
Identifying ways to preserve their ability to remove waste and regulate inflammatory responses could therefore help scientists develop new approaches to protecting brain health.
However, the study does not establish that TIMP2 prevents Alzheimer’s disease, reverses dementia or restores memory in humans. Its reported benefits relate primarily to changes in microglial function in mice.
Castellano said the research provides new insights into how youth-associated factors influence biological pathways involved in brain ageing and age-related neurological disorders, potentially informing future therapeutic strategies.
The research team included Brittany Hemmer, who was a graduate student in Castellano’s laboratory during the study.
The work received support from the United States National Institute on Aging and the Cure Alzheimer’s Fund, among other research funding sources.
Human studies still needed
Despite the encouraging findings, researchers say more work is required before TIMP2 can be considered a potential treatment for age-related brain disorders.
Future studies will need to establish whether the protein produces comparable effects in humans, identify how it acts on brain immune cells and determine the safety of interventions designed to increase its activity.
Scientists will also need to investigate whether improvements in microglial function translate into meaningful benefits for memory, thinking and other measures of cognitive health.
For now, the study adds to growing scientific interest in the biological factors that help preserve brain function during ageing.
If future research confirms the findings in humans, TIMP2 or the pathways it regulates could provide new targets for therapies designed to maintain brain health and address age-related neurological decline.
