How Neuroimmunology Is Redefining Brain Aging and Repair
Understanding the brain–immune ecosystem in aging reveals targets for Alzheimer’s immunotherapy.
The interdependence between the brain and the immune system is essential for lifelong brain health. This article explores how understanding the brain–immune ecosystem brings insights to the molecular mechanisms behind brain aging, facilitating research into immunotherapies for neurodegenerative diseases.
The brain’s resident immune cells vs infiltrating immune cells
Microglia are immune cells that reside in the central nervous system (CNS), constantly sensing and responding to pathogens and damage. It was long believed that these immune cells were sufficient for CNS protection, but Professor Michal Schwartz and her team from the Weizmann Institute of Science were the first to demonstrate that monocyte-derived macrophages are also needed to support repair in cases of severe CNS injury.
“This series of findings was initially greeted with a high degree of skepticism,” Schwartz told Technology Networks. “The field has now developed to acknowledge the role of macrophages recruited from the circulation.”
“For decades, the brain was thought to be completely isolated from the immune system,” Schwartz said. However, her team were the first to demonstrate that “healthy brain plasticity, including neurogenesis, cognitive performance and the ability to cope with stress, is tightly dependent on the immune system.”
Alongside macrophages, bone marrow-derived T cells are also critical for brain function, protection and repair. T cells that recognize brain self-antigens are key for protective autoimmunity, which helps to repair and maintain tissue integrity.
Peripheral immune cells reside in specialized niches at the brain’s borders, where they can remotely influence brain function without interfering with neuronal networks.
“Effective CNS–immune cross-talk is essential for lifelong brain function, and depends on the integrity of both systems,” said Schwartz. “When this balance is lost, the two systems enter into a feed-forward loop, exacerbating dysfunction.”
The autonomic sympathetic nervous system links the brain to the systemic immune system through the activation of the spleen, bone marrow and other immune organs. Signaling from the brain to the immune system may also occur via soluble mediators in the bloodstream or cerebrospinal fluid.
“The gut–brain axis represents another key route of immune–neural communication,” Schwartz explained.
Bacteria in the gut produce metabolites, including short-chain fatty acids, which can activate the immune system and autonomic nervous system to influence the brain indirectly.
When the balance of bacteria in the gut is disrupted, a local inflammatory response can escalate into peripheral inflammation when inflammatory mediators enter systemic circulation. The integrity of the blood–brain barrier is influenced by peripheral inflammation, which allows immune cells and inflammatory mediators into the central nervous system. Proinflammatory cytokines from the periphery can also activate microglia.
The gut-brain immune connection also works in reverse – when the CNS is injured or damaged, the resident microglia are activated, initiating a process resulting in the recruitment of peripheral immune cells. These cells produce proinflammatory cytokines, which can reach the intestinal barrier and evoke gut inflammation.
The brain–immune connection in aging
When the brain was still thought to be isolated from the immune system, aging of the brain was thought to be brain-centric. However, now we know that the immune system is critical for brain function, “it is clear that immune aging accelerates brain aging,” said Schwartz.
“While aging of the immune system is not the primary cause of neurodegenerative diseases, immune aging or dysfunction can definitely serve as a catalyst of disease exacerbation,” she continued.
Schwartz and her team discovered that brain aging is related to brain-immune interface dysfunction. “Specifically, we identified an IFN-I response program in the aging choroid plexus,” she said.
The choroid plexus is an interface between the brain and the circulation, where T cells reside. During aging, brain-derived signaling activates type 1 interferon signaling at the choroid plexus to mitigate inflammation in the brain. However, “its persistent expression becomes detrimental to brain plasticity, in part by impairing the ability of microglia to cope with inflammatory conditions,” said Schwartz.
In Alzheimer’s disease (AD), “chronic exposure to threatening conditions results in microglial exhaustion and even senescence, which leads to a local brain inflammation, driving disease progression,” Schwartz explained.
When microglia are not functioning optimally, macrophages from the circulation are essential for supporting the brain. These macrophages can resolve inflammation and remove damage-associated proteins. However, their spontaneous recruitment is not sufficient to cope with the disease. Enhancing the recruitment of circulating macrophages forms an avenue of research in AD treatment.
Immunotherapy for Alzheimer’s
AD is characterized by the buildup of misfolded amyloid and tau proteins, which have been the primary target for therapeutics. Individuals exhibiting amyloid and tau aggregation can remain asymptomatic for more than a decade, and once the disease becomes symptomatic, local brain inflammation becomes a driving force of disease progression.
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To resolve local inflammation, recruitment of monocyte-derived macrophages and regulatory T cells from the periphery is essential.
“Since aging is a major risk factor for AD, we proposed that boosting the immune response might restore its ability to support and protect the brain,” Schwartz explained.
The process by which macrophages and T cells home in on inflammation can be enhanced by boosting protective autoimmunity or by reducing systemic immune exhaustion.
“One such approach involves blocking inhibitory immune checkpoint pathways, such as the PD-1/PD-L1 axis,” said Schwartz. “Specifically, systemic administration of PD-L1 blocking antibody, administered intermittently, triggers a cascade of immunological events, beginning outside the brain and culminating within it.”
“This treatment led to a reduction in local brain inflammation as the primary effect in multiple mouse models of neurodegeneration, including amyloidosis, tauopathy, Parkinson’s disease and Huntington’s disease,” she said. “This was subsequently followed by improvements in several pathological markers within the brain that contribute to functional decline.”
The future of research
At the Society for Neuroscience annual meeting 2025, Schwartz will give a lecture in which she will also describe her personal scientific journey, exploring how she has worked to challenge a long-held scientific dogma. “When I started my lab as a new principal investigator, the prevailing belief was that the brain is completely isolated from the immune system,” she said. “Yet I chose to challenge this view because it did not make sense to me that an organ as vital as the brain would have evolved to lose the ability to receive assistance from the body’s own repair mechanism, the immune system.”
“Persistence, resilience and facts rather than words, eventually revolutionized the field, to the extent that the current question is no longer whether, but how, to harness the immune system to help the brain.”
Professor Michal Schwartz was speaking to Katie Brighton, Science and Newsletter Writer for Technology Networks.
