Alleviating age-related cognitive decline by activating immune cells

purple brain
Researchers at Albany Medical College have discovered that targeting ILC2 immune cells in aged brains might open up new avenues for treating age-related cognitive decline and neurodegenerative diseases. (Raman Oza/Pixabay)

Interleukins IL-33 and IL-5 are major culprits in the inflammatory responses associated with asthma. But researchers at Albany Medical College just found that leveraging the ability of these two signaling molecules to link to a type of immune cell in the brain might alleviate age-related cognitive decline and help treat neurodegenerative diseases.

The class of immune cell is called group 2 innate lymphoid cells (ILC2s). In a new study published in the Journal of Experimental Medicine, the scientists reported that treating old mice with IL-33 to activate ILC2 or use IL-5—which is a product of ILC2 activation—improved cognition among the animals.

In healthy mice, ILC2s were recently found in the meninges—the membranes that line the skull and enclose the brain and spinal cord. These cells were shown to be activated and help healing after spinal cord injury. “However, whether ILC2s also reside in other parts of the central nervous system, and how they respond to aging, was unknown,” Qi Yang, the new study’s co-corresponding author, said in a statement.

Yang and colleagues examined the brains of mice of different ages. They found that in aged mice, ILC2s made up about 50% of all immune cells in a complex cerebral structure called the choroid plexus. But there were only a few in young mice. An analysis of choroid plexus tissue also revealed that ILC2s exist in large numbers in elderly people.

Choroid plexus produces cerebrospinal fluid and acts as a barrier that blocks toxins from entering the central nervous system. It’s close to the hippocampus, a part of the brain that’s crucial to learning and memory functions.

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ILC2s in aged mice brains were largely inactive. To determine whether they would be able to proliferate, the researchers treated mice with IL-33, a known ILC2 activator. As a result, the ILC2s significantly expanded, and the researchers noted that they expressed high amounts of Ascl2 and Hif1a, the transcription factors that promote the renewal and survival of neurons. ILC2s in older mice also survived longer than did those in younger rodents.

What’s more, aged mice that received pre-activated ILC2 or IL-33 showed significantly enhanced performance in tests that measured the animal’s cognitive functions, such as spatial memory, the team reported. “Together, these data provide direct evidence that activated ILC2 can improve the cognitive function of aged mice,” the researchers wrote in the study.

The team went on to examine the specific effector molecules by which activated ILC2 work to improve cognitive function. They tried giving the mice either IL-5 or IL-13, two signaling molecules ILC2s produce. While IL-13 has been shown to promote spatial learning and memory in young mice, IL-5’s effects on cognition were unknown.

Surprisingly, it was IL-5, not IL-13, that improved elderly animals’ performance in tests. The team found that treatment with IL-5 increased neurogenesis and reduced neuroinflammation, which probably explains why they showed better cognitive function.

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Neurodegenerative diseases and age-related dementia represent huge unmet medical needs, so scientists have been searching for new pathways to combat them. A team led by Brown University scientists previously found that widely used HIV drug lamivudine might be repurposed to treat age-related disorders by limiting the activity of a virus-like mechanism that gives rise to an inflammatory immune response.

In 2018, a collaboration between the University of Virginia and Virginia Tech found that meningeal lymphatic vessels, which connect the brain and the immune system, could be targeted for Alzheimer’s and age-related dementia.

The Albany Medical College team believes ILC2s in the aged brain are also promising targets for treating age-related cognitive decline and neurodegenerative diseases.

“Our work has thus revealed the accumulation of tissue-resident ILC2 cells in the choroid plexus of aged brains and demonstrated that their activation may revitalize the aged brain and alleviate aging-associated cognitive decline,” said Yang.