Despite being the most common form of dementia, there is still so much scientists don’t understand about Alzheimer’s disease. Research out today might provide a vital clue to unraveling its origins.
Researchers at the Washington University School of Medicine studied mice modeled to have Alzheimer’s-like illness. They found evidence that certain immune cells linked to Alzheimer’s are actually goaded on by other cells outside the brain. The discovery could very well help us find more effective treatments that can short-circuit this process, the researchers say.
“This means that we not only have to look at Alzheimer’s in the brain, we have to look outside as well; that we should be looking at this more systemically,” lead author Hao Hu, a postdoctoral fellow at WashU, told Gizmodo. “This is a disease that affects the brain, but the whole body is actually getting involved.”
An immune system turned foe
The brains of people with Alzheimer’s become cluttered with the misfolded forms of two proteins, amyloid beta and tau. Many researchers have long argued that amyloid beta in particular drives the brain’s destruction. But this hypothesis has looked much shakier lately, or at least more complicated than hoped. The newest anti-amyloid treatments today have only shown modest benefits at best in slowing down the progression of Alzheimer’s, for instance.
The WashU team’s earlier work has pointed to another possible key driver of Alzheimer’s symptoms: the accumulation of certain immune cells known as T cells in the brain. While the build-up of amyloid and tau could still be a crucial early aspect of Alzheimer’s, high levels of T cells, likely in conjunction with another type of immune cell called microglia, in the brain might be instigating the actual damage, they argue. In a previous mouse study, the same researchers eliminated or blocked the activity of these T cells, which seemed to reduce further inflammation and neurodegeneration.
T cells are often activated by another kind of immune cell called dendritic cells, and the researchers were especially interested in a type called the classic or conventional dendritic cell. There are relatively few of these dendritic cells in the brain, however, and those that are there didn’t seem to be responsible for the T cell-related damage seen in the Alzheimer’s brain, the team’s past research had suggested. So they decided to look for the potential source somewhere else.
In this new study with mice, the researchers genetically knocked out the presence of dendritic cells from lymph nodes outside the brain as well as other locations. When they did, it seemingly prevented the build-up of high T cell levels in the brain. What’s more, it also appeared to reduce the mice’s expected brain damage while their cognition remained normal. Notably, these improvements were still seen despite levels of abnormal tau not decreasing in the mice’s brains. The team’s findings were published Thursday in the journal Nature Neuroscience.
What next?
These findings are only in mice, so it will take further research to conclusively show that dendritic and T cells are relevant drivers of Alzheimer’s in humans. And there are still unanswered questions about this hypothesis, such as what might trigger dendritic cells to send T cells after the brain in the first place. That said, the researchers do suspect that abnormal tau accumulation in the brain is a key trigger.
Assuming this work continues to bear fruit, it might eventually lead to new strategies against Alzheimer’s. One reason why Alzheimer’s is so hard to treat is that many promising drug candidates can’t even reach the brain due to the brain-blood barrier. But if there’s a vital instigator of Alzheimer’s outside the brain, then it should be easier and safer to find ways to disable that target.
“It might not completely reverse the disease, but it could delay it significantly,” Hao said. Importantly, he adds, Alzheimer’s is far from the only neurodegenerative disorder strongly linked to abnormal tau, so this research could have even wider implications.
The team next plans to test whether eliminating dendritic cells later in life can still reduce brain damage in mice—a strategy that more mimics potential treatments we’d use in older people at risk of Alzheimer’s. They also plan to study if it’s possible to selectively target only certain lymph nodes (particularly those around the neck) and still get a benefit, which would likely help reduce side effects.
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