Research by scientists at Washington University School of Medicine in St. Louis has shown how brain-resident immune cells known as microglia may partner with T cells to cause neurodegeneration in Alzheimer’s disease.

Studying mice with Alzheimer’s-like damage in their brains caused by the protein tau, the researchers discovered that microglia attract powerful cell-killing T cells into the brain, and that most of the neurodegeneration could be avoided by blocking the T cells’ entry or activation. The findings suggest that targeting T cells may represent a new approach to preventing neurodegeneration and treating Alzheimer’s disease and tauopathies.

“This could really change the way we think about developing treatments for Alzheimer’s disease and related conditions,” said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III distinguished professor of neurology. “Before this study, we knew that T cells were increased in the brains of people with Alzheimer’s disease and other tauopathies, but we didn’t know for sure that they caused neurodegeneration. These findings open up exciting new therapeutic approaches.”

Some widely used drugs target T cells, Hotzman continued. “Fingolomid, for example, is commonly used to treat multiple sclerosis, which is an autoimmune disease of the brain and spinal cord. It’s likely that some drugs that act on T cells could be moved into clinical trials for Alzheimer’s disease and other tauopathies if these drugs are protective in animal models.”

Holtzman and colleagues reported on their findings in Nature, in a paper titled, “Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy,” in which they concluded, “Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T-cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies.”

Along with Holtzman, the research team included first author Xiaoying Chen, PhD, an instructor in neurology, together with Maxim N. Artyomov, PhD, the alumni endowed professor of pathology & immunology, and Jason D. Ulrich, PhD, an associate professor of neurology, and colleagues.

Alzheimer’s develops in two main phases. First, plaques of amyloid-β protein start to form. The plaques can build up for decades without obvious effects on brain health. But eventually, tau also begins to aggregate, signaling the start of the second phase. From there, the disease quickly worsens: The brain shrinks, nerve cells die, neurodegeneration spreads, and people start having difficulty thinking and remembering. As the authors summarized, “Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease.”

Nearly two dozen experimental therapies targeting the immune system are in clinical trials for Alzheimer’s disease, a reflection of the growing recognition that immune processes play a key role in driving the brain damage that leads to confusion, memory loss, and other debilitating symptoms. “Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases,” the authors wrote. However, they acknowledged, “So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology.”

Many of the immunity-focused Alzheimer’s drugs under development are aimed at microglia, the brain’s resident immune cells, which can injure brain tissue if they’re activated at the wrong time or in the wrong way. The authors further explained, “Neuroinflammation is present in the brain of individuals with Alzheimer’s disease, and many studies focus on the cellular and molecular changes and the role of microglia, a key component of the innate immune response in the brain during the development and progression of Alzheimer’s disease.”

Microglia and their role in Alzheimer’s have been intensely studied. The cells become activated and dysfunctional as amyloid plaques build up, and even more so once tau begins to aggregate. Microglial dysfunction worsens neurodegeneration and accelerates the course of the disease.

Chen wondered about the role of other, less-studied immune cells in neurodegeneration. For the reported study, Chen and colleagues analyzed immune cells in the brains of mice genetically engineered to mimic different aspects of Alzheimer’s disease in people, looking for changes to the immune cell population that occur over the course of the disease. “ … we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration,” the team commented.

They found that, mirroring the early phase of the disease in people, two of the mouse strains build up extensive amyloid deposits but do not develop brain atrophy. A third strain, representative of the later phase, develops tau tangles, brain atrophy, neurodegeneration, and behavioral deficits by 9.5 months of age. A fourth mouse strain that does not develop amyloid plaques, tau tangles, or cognitive impairments was studied for comparison.

The researchers found many more T cells in the brains of tau mice than in the brains of amyloid or comparison mice. Notably, T cells were most plentiful in the parts of the brain with the most degeneration and the highest concentration of microglia. T cells were similarly abundant at sites of tau aggregation and neurodegeneration in the brains of people who had died with Alzheimer’s disease. “We also discovered adaptive immune responses in both a mouse model of tauopathy and brain samples from patients with Alzheimer’s disease, finding that T cells are present in the brain parenchyma and also that their enrichment highly correlates with the severity of brain atrophy.”

Additional mouse studies indicated that the two kinds of immune cells work together to create an inflammatory environment primed for neuronal damage. Microglia release molecular compounds that draw T cells into the brain from the blood and activate them; T cells release compounds that push microglia toward a more proinflammatory mode.

Eliminating either microglia or T cells broke the toxic connection between the two and dramatically reduced damage to the brain. For example, when tau mice were given an antibody to deplete their T cells, they had fewer inflammatory microglia in their brains, less neurodegeneration and atrophy, and an improved ability to perform tasks such as building a nest and remembering recent things. “Removal and modulation of T cells rescued the brain atrophy and highlighted that T cells have an important role in neurodegeneration,” the scientists stated. The collective results, they noted, offer up “…  direct evidence that breaking the neurodegeneration-associated immune hub between activated microglia and infiltrated T cells effectively prevents neurodegeneration and decreases cognitive decline.”

“What got me very excited was the fact that if you prevent T cells from getting into the brain, it blocks the majority of the neurodegeneration,” Holtzman said. “Scientists have put a lot of effort into finding therapies that prevent neurodegeneration by affecting tau or microglia. As a community, we haven’t looked at what we can do to T cells to prevent neurodegeneration. This highlights a new area to better understand and therapeutically explore.”

The authors further noted, “Mapping the disease-state-specific interlink between microglia and T cells, including their signaling communications, presented antigens, and pathophysiological responses, will be a key nexus to set up unique therapeutic interventions to prevent or reverse brain atrophy and neurodegeneration in tauopathies.”

In an accompanying News and Views, Ian H. Guldner, PhD, and Tony Wyss-Coray, who are in the department of neurology and neurological sciences, and at the Wu Tsai Neurosciences Institute, Stanford University School of Medicine, commented that the newly reported study “…  adds to a growing body of research indicating that specialized T cells in the brain not only are essential for physiological functions but also have regulatory and toxic roles in aging and neurodegeneration.”

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