Alzheimer’s disease is characterized by the loss of functional neurons in the brain. But what causes this loss? A new study reveals that people with Alzheimer’s disease have an abundance of newly acquired mutations in neurons — more than people of the same age without Alzheimer’s disease, enough to disrupt genes important for brain function.
“Cells have repair pathways to undo DNA damage, but in Alzheimer’s, neurons can’t keep up with the repairs,” says Christopher Walsh, MD, PhD, chief of genetics and genomics at Boston Children’s Hospital and lead researcher. In the study. So the damage is permanent and cumulative. This work provides a new way of thinking about neurodegenerative diseases such as Alzheimer’s disease, suggesting that they impair the ability of neurons to use their genomes.”
The study published in temper nature On April 20, it may also help connect the dots between neuronal loss and the well-documented accumulation of amyloid beta and tau proteins in Alzheimer’s disease.
DNA damage escalates in Alzheimer’s disease
As we age, our neurons naturally acquire mutations. The researchers, led by first authors August Yue Huang, MD, PhD from Boston Children’s Hospital, and Michael B. Miller, MD, of Boston Children’s and Brigham and Women’s Hospital, explains how this process might differ in Alzheimer’s disease. To find out, they analyzed whole-genome sequencing data from 319 individual neurons from the prefrontal cortex and hippocampus of people with Alzheimer’s disease and people with the neurotype of the same age.
Not only did people with Alzheimer’s disease have more mutations in cognitively important brain regions, but the pattern of mutations was different from that in typically aging brains. The changes — the switches in certain bases or “letters” of DNA — were of a kind known to be caused by reactive oxygen species (ROS), chemicals that can oxidize and damage DNA. The team also found direct evidence of increased oxidation in the neurons of people with Alzheimer’s disease.
This is where amyloid beta and tau may come in. Both can stimulate the production of ROS, which is increased in the brains of people with Alzheimer’s disease. Huang says microglia, which are immune cells in the brain that show abnormal activity in Alzheimer’s disease, could also play a role. “Microglia-induced neuroinflammation may be one cause of oxidative damage to the genome,” he says.
The researchers note that genes important for brain function may be particularly susceptible to mutations. These genes tend to be larger than average, presenting a target that is more likely to be ‘hit’ and disrupted. They are also often turned on.
“Genes with a higher level of expression in the brain – and therefore more likely to have critical functions – have a higher mutation burden,” Huang says.
Effects of Alzheimer’s treatment?
It’s tempting to speculate that antioxidants could have value in Alzheimer’s disease. The researchers want to further investigate how genome oxidation occurs and the role that inflammation and immune reactions may play.
“We want to look at other neurodegenerative diseases like frontotemporal dementia, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy to see if there is a limit to the number of mutations in the brain that neurons can tolerate,” Walsh says. We have demonstrated that in Alzheimer’s disease, neurons cannot tolerate genome-wide oxidation. This results in permanent, irreparable damage.”
Walsh, MD, a researcher at the Howard Hughes Medical Institute, was a co-principal investigator on the study with Eunjung Alice Lee, PhD, of Boston Children’s Hospital, and Michael Lodato, PhD, of the University of Massachusetts Medical School.
Learn more about the research in the Department of Genetics and Genomics at Boston Children’s Hospital.