By Devin Powell
As we grow older, the cells that produce our blood tend to acquire damage to their DNA.
These mutations are harmless most of the time. But certain changes can cause some of us, up to 30 percent of those over the age of 70, to be at risk of disease. They make people prone to blood cancer and dying early from a heart attack or stroke. They increase the risk of atherosclerotic cardiovascular disease, in which our white blood cells fail to properly maintain our blood vessels.
Blood expert Siddhartha Jaiswal, M.D., Ph.D., had a hunch that these age-related mutations might also play a role in Alzheimer’s disease, which has been linked to problems with white blood cells that maintain the brain. But when he and his colleagues examined the DNA of people with and without the neurodegenerative disease, they found something unexpected. The same cellular mutations that were dangerous for diseases of the blood seemed to protect against this disease of the brain, Alzheimer’s.
“The result was so surprising that we didn’t believe it at first,” said Jaiswal, an assistant professor of pathology at Stanford and member of the Wu Tsai Neurosciences Institute. “After checking the results, though, we are confident: If you have these mutations, you’re less at risk for Alzheimer’s.”
The research, published online June 15 in Nature Medicine, has also begun to uncover how these mutations bolster the brain: offering a potential new wellspring of insight for scientists trying to figure out how to slow the progression of dementia.
Jaiswal’s team will continue their exploration of the subject with support from the Phil and Penny Knight Initiative for Brain Resilience at Wu Tsai Neuro, which is advancing transformative new ideas to promote healthy brain aging and resilience against neurodegenerative diseases.
Stem cells in our bodies constantly make blood cells, including the red blood cells that carry oxygen and the white blood cells that fight off disease. This process, called hematopoiesis, takes place in the marrow of our bones. There, the stem cells divide and differentiate, passing on their DNA and their mutations to the blood cells they create.
The age-related mutations studied by Jaiswal’s team tend to affect a specific set of genes in stem cells. This causes a small number of stem cells to play an outsized role in hematopoiesis, to contribute a greater percentage of blood cells than they usually would. Doctors call this condition clonal hematopoiesis of indeterminate potential, or CHIP for short.
To explore CHIP in the context of Alzheimer’s disease, Jaiswal examined subjects recruited for heart studies, including about two hundred people who went on to have Alzheimer’s. He discovered that those with the CHIP mutations were 30 to 40 percent less likely to develop the neurodegenerative disease compared to those without the mutations. To confirm this finding, Jaiswal then investigated a group in another study, this one including more than a thousand people with Alzheimer’s disease. Again, those with CHIP were about a third as likely to develop Alzheimer’s than those without.
Surprising as the numbers were, they were solid. So the team started digging deeper.
“Once the statistics showed a clear result, we wanted to look in the brains of people with CHIP to find clues about exactly what was going on,” said lead author Hind Bezoud, Ph.D., a former postdoctoral research fellow at Stanford Medicine.
Specifically, the researchers wanted to know if blood cells bearing the CHIP mutations could be found in the brain. So they acquired postmortem brain tissue from several donors known to have CHIP, as well as some donors without CHIP. The scientists dissolved samples of the tissue, leaving only free-floating nuclei containing DNA. Sequencing of this genetic material revealed the CHIP mutations, inside nuclei bearing signatures of blood cells.
Jaiswal’s team then set out to determine which of the many blood cell types their CHIP mutations resided in. To identify a cell’s type, scientists usually profile its RNA, which indicates which genes have been switched on and off. But the RNA of Jaiswal’s brain tissue samples had not survived the flash-freezing process used to preserve the tissue.
“We had to get creative and use a technical trick, as well as a lot of sophisticated computational analysis,” said Julia Belk, Ph.D., a Stanford postdoctoral researcher from the lab of Howard Chang and author on the new paper.
Belk used a newer technique to examine modifications made to the DNA itself that reveal which genes are switched on and off. This allowed them to sort out different blood cells and narrow the CHIP mutations to one particular type: microglia, the white blood cells that serve as the immune system of the brain.
Finding microglia derived from bone marrow stem cells with mutations related to old age was also a surprise for the scientists. Traditional wisdom holds that our brains acquire all their microglia when we’re in the womb, through a process that has nothing to do with adult hematopoiesis. But the researchers found that a whopping 30 to 90 percent of all microglia in the brain came from bone marrow precursors.
“This goes against decades of established dogma suggesting that we don’t make new microglia as adults,” said Thomas Montine, M.D., Ph.D., a Stanford professor of pathology and co-senior author on the new paper. “Now, we want to know what those microglia are doing.”
Jaiswal’s team has answered one question, with an answer that makes unexpected connections between aging, blood cells and brain disease. But his work brings up new questions. How do mutated microglia curb the onset of Alzheimer’s? Are they better at stopping the neurodegenerative disease early? Are they tougher, able to survive to fight longer? And how can we leverage this knowledge to fight and prevent disease?
Supported by an innovation award from the Knight Initiative, Jaiswal is focused on answering these questions. This award will enable the team to look more closely at how the mutated microglia differ from their normal counterparts in samples of human brain tissue as well as in experimental models.
“If we can figure out what’s going on, we might be able to harness this biology,” said Jaiswal, co-senior author on the paper. “As a physician-scientist, I’m interested in understanding how we can use this information for the benefit of human health.”