Alzheimer’s Disease Threat May Emerge From Beyond The Brain, Study Finds

We usually think of Alzheimer’s as a brain disease, but a growing body of evidence shows it’s more complicated than that. Indeed, some of the damage caused by the condition appears to emerge not from inside the brain, but outside it. A new study published in Nature Neuroscience suggests that an immune response from beyond the brain could end up attacking it, causing the neurodegeneration we see in Alzheimer’s disease.

But fresh findings published in the journal Nature Neuroscience suggest that neurodegeneration may be connected to an immune response originating outside the central nervous system. In previous research by some of the same team, scientists discovered that immune cells called T cells were implicated in this chain of events, being found in abundance in the brains of mice that also showed high levels of tau, one of the two key proteins associated with Alzheimer’s disease. That study showed that when researchers eliminated or blocked the T cells in mice, it reduced neuronal damage, suggesting that manipulating the immune cells could be a new avenue for prospective treatments.

Until not that long ago, most people, including myself, did not think that the immune response was even involved in neurodegenerative diseases that are due to protein accumulation in the brain, says neurologist David Holtzman from Washington University in St. Louis, the senior author of both studies. We've shown they're important, and that they are a potential target for future therapy.

How Peripheral Immune Cells Reach the Brain

What wasn’t clear from the earlier research, though, was why these T cells were being activated in the first place, and how they were finding their way to the brain. The newly published findings have offered up some answers.

The current discovery builds on earlier work demonstrating that immune cells known as T cells are found in abundance inside the brains of mice exhibiting high levels of tau protein. When scientists experimentally eliminated or blocked those T cells in earlier laboratory tests, the resulting neuronal damage dropped significantly. However, the origin of those cells and the trigger for their journey remained a mystery until now.

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The updated findings show that a specific form of T cells called CD8+ T cells, which normally kill cancerous, harmful, or abnormal cells, can be directed to enter the brain, due to interactions with cells called conventional type 1 dendritic cells (cDC1s). cDC1s act as sentinels in the immune system, identifying potential targets in the body based on molecular signatures, and then signaling the detection to CD8+ T cells, which go in for the kill. This identification process, called cross-presentation, basically primes CD8+ T cells to execute their immune function, but it also appears to contribute to neurodegeneration if the T cells find their way into the brain.

David Holtzman, neurologist at Washington University in St. Louis

In mice engineered to develop tau pathology, experimentally eliminating the cDC1 sentinel cells – or disrupting their cross-presentation ability – appeared to substantially reduce signs of neurodegeneration and neuroinflammation compared to tau mice whose cDC1 functions were left unimpaired. Experiments also showed that silencing cDC1 functions in mice substantially reduced the number of CD8+ T cells that ended up in animals’ brains, suggesting the priming by cDC1 cells plays a crucial role in enabling CD8+ T cells to infiltrate the brain. Interestingly, altering the mice’s cDC1 cells didn’t substantially change the amount of tau in the animals’ brains, suggesting that while the neurodegeneration is related to tau accumulation, the immune response itself may be the more important driver of brain damage.

The Role of Deep Cervical Lymph Nodes

One of the more puzzling aspects of the earlier research was that cDC1s themselves were rarely detected in the brain, even in experiments showing severe degeneration, which led the researchers to hypothesize that the cDC1 signaling to CD8+ T cells had to be occurring outside the brain. This discrepancy led investigators to hypothesize that the crucial priming interaction had to be occurring elsewhere in the body.

Subsequent experiments confirmed that CD8+ T cells are activated inside lymph nodes in the neck called deep cervical lymph nodes. Recent evidence shows deep cervical lymph nodes could play a huge and overlooked role in neurological diseases like Alzheimer’s, if their function as a drainage for waste products from the brain falters.

We propose that tauopathy induces neuronal injury, resulting in the release of antigens that are captured by cDC1s to prime CD8+ T cells, the researchers write in their paper. These observations strongly suggest antigen presentation by cDC1s occurs predominantly outside the brain.