Alzheimer's Study Reveals an Immune Attack Beyond the Brain

Alzheimer's is commonly regarded as a disease of the brain, yet a growing body of evidence indicates that the picture is more complex.

Some of the harm linked to the condition may, in fact, begin beyond the brain rather than within it.

A new study in Nature Neuroscience indicates that an immune reaction originating outside the brain may subsequently attack it, driving the neurodegeneration associated with Alzheimer's disease.

Earlier work by several members of the same research team found that immune cells known as T cells were involved in this sequence. They were present in large numbers in the brains of mice with elevated levels of tau, one of the two principal proteins connected with Alzheimer's disease.

That research found that removing or blocking T cells in mice lessened neuronal damage, indicating that altering these immune cells could represent a possible route for future 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 immune cells may reach the Alzheimer's brain

The previous study did not establish what activated these T cells initially, or how they managed to reach the brain.

The latest results provide some potential explanations.

In mouse experiments, the researchers showed that a particular form of T cell, CD8+ T cells, can be prompted to enter the brain through interactions with cells called conventional type 1 dendritic cells (cDC1s). Normally, CD8+ T cells destroy cancerous, harmful or abnormal cells.

Within the immune system, cDC1s serve as sentinels: they recognise potential targets in the body from their molecular signatures, then communicate that detection to CD8+ T cells, which carry out the killing.

This recognition mechanism, known as cross-presentation, effectively prepares CD8+ T cells to perform their immune role. However, it also seems capable of contributing to neurodegeneration when the T cells enter the brain.

In mice engineered to develop tau pathology, experimentally removing the sentinel cDC1 cells - or interfering with their cross-presentation capacity - appeared to markedly lessen evidence of neurodegeneration and neuroinflammation. This was compared with tau mice in which cDC1 activity remained intact.

The experiments further revealed that suppressing cDC1 activity in mice greatly reduced the number of CD8+ T cells found in the animals' brains. This suggests that priming by cDC1 cells is critical in allowing CD8+ T cells to infiltrate the brain.

Notably, changing the mice's cDC1 cells did not substantially alter the amount of tau in their brains. This indicates that although neurodegeneration is associated with tau build-up, the immune response itself may be the more significant force behind brain damage.

Deep cervical lymph nodes and neurodegeneration

A further puzzle was that cDC1s themselves were seldom found in the brain, including in experiments that showed severe degeneration. The researchers therefore proposed that cDC1 signalling to CD8+ T cells must occur outside the brain.

A separate experiment seemed to support this explanation, finding evidence that CD8+ T cells were activated in neck lymph nodes known as deep cervical lymph nodes.

Recent evidence suggests that deep cervical lymph nodes may have a major, underappreciated part in neurological illnesses such as Alzheimer's if their role in draining waste products from the brain becomes impaired.

Exactly what is happening remains unclear, but Holtzman's team has developed a theory that brings many of these findings together.

"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."

Put another way, the team suggests that tau accumulating in the brain may lead to the release of antigens. Those antigens could then travel downstream to the deep cervical lymph nodes.

There, they activate cDC1s, which notify CD8+ T cells. The T cells then travel back upstream to the brain, where they ultimately produce neuroinflammation and neurodegeneration.

Potential treatment routes beyond the brain

More research will be required to verify this hypothesis. However, the findings are promising because they open up previously unexplored treatment possibilities for Alzheimer's and related conditions: targeting the brain's lymphatic processes rather than the brain itself.

"One of the issues in developing treatments for neurological diseases is that you need to engineer your treatment so that it gets into the brain and past the blood-brain barrier, but we might not actually need to get the drugs into the central nervous system to mitigate neurodegeneration," Holtzman says.

"There are lots of ways to manipulate T cells that have been studied extensively and that are approved treatments for other diseases, but many haven't yet been explored for neurodegenerative diseases."

The findings are reported in Nature Neuroscience.

This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. Although we take pride in our process, we are only human. If you notice an error, please let us know.