We typically view Alzheimer’s disease as a brain disorder, but growing evidence suggests it is a far more complex condition. Indeed, some of the damage caused by the disease appears to originate outside the brain rather than within it.
A new study published in the journal Nature Neuroscience suggests that an immune response originating outside the brain can ultimately attack it, triggering the neurodegeneration observed in Alzheimer’s disease.
Previous research by the same team revealed that immune cells known as T cells play a role in this chain of events; these cells are found in large numbers in the brains of mice that also exhibit high levels of tau protein—one of the two key proteins associated with Alzheimer’s disease.
That study showed that eliminating or blocking T cells in the mice reduced neuronal damage, suggesting that manipulating immune cells could open up new avenues for promising treatments.
“Until quite recently, most people—myself included—did not think the immune response played any role in neurodegenerative diseases caused by protein accumulation in the brain,” says neurologist David Holtzman of Washington University in St. Louis, the lead author of both studies. “We have shown that they are important and represent a potential target for future therapies.”
However, previous studies left it unclear why these T cells become activated in the first place and how they enter the brain.
Recently published research findings have provided some answers. In experiments involving mice, researchers discovered that a specific type of T-cell—known as CD8+ T-cells, which typically eliminate cancerous, harmful, or abnormal cells—can be directed to the brain through interactions with cells called conventional type 1 dendritic cells (cDC1).
cDC1s act as sentinels within the immune system; they recognize potential targets in the body based on molecular signatures and then relay this detection signal to CD8+ T-cells, which subsequently carry out the destruction.
This identification process, known as cross-presentation, essentially primes CD8+ T-cells to perform their immune functions; however, it appears to also contribute to neurodegeneration if the T-cells enter the brain.
In mice genetically engineered to develop tau pathology, the experimental depletion of cDC1 sentinel cells—or the disruption of their cross-presentation capabilities—resulted in a significant reduction in signs of neurodegeneration and neuroinflammation compared to mice with tau pathology whose cDC1 functions remained intact.
The experiments also demonstrated that suppressing cDC1 function in mice substantially reduced the number of CD8+ T-cells entering the brain, suggesting that priming by cDC1 cells plays a crucial role in enabling CD8+ T-cell infiltration into the brain.
Interestingly, altering cDC1 cells in the mice did not lead to a significant change in the levels of tau protein in the brain; this suggests that while neurodegeneration is associated with tau accumulation, the immune response itself may be a more critical factor in brain damage. Another puzzle was that cDC1 cells themselves were rarely found in the brain—even in experiments showing severe degeneration—leading researchers to hypothesize that cDC1 signaling to CD8+ T cells must occur outside the brain.
A separate experiment appeared to confirm this, providing evidence of CD8+ T cell activation in the lymph nodes of the neck known as deep cervical lymph nodes.
Recent studies indicate that deep cervical lymph nodes can play a massive and often underestimated role in neurological conditions like Alzheimer’s disease if their function of draining metabolic waste products from the brain is impaired.
We do not yet fully understand what is happening here, but Holtzman’s team has a theory that ties many of the threads together.
“We propose that tauopathy causes neuronal damage, resulting in the release of antigens that are captured by cDC1 cells to activate CD8+ T cells,” the researchers write in their paper. “These observations strongly suggest that antigen presentation by cDC1 dendritic cells occurs primarily outside the brain.”
In other words, the researchers suggest that as tau protein accumulates in the brain, antigens may be released and travel further afield, to…
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