Scientists have discovered how two major groups of genes contribute to the neurodegeneration seen in dementia, a finding that brings them closer to uncovering new drug therapies that could stop or slow the disease’s progression.
Researchers at the University of California, Los Angeles, found two major groups of genes tied to mutations that cause an overproduction of tau, a protein that many researchers believe causes brain cells to die in certain forms of dementia. The recent study, published in the journal Nature Medicine, was primarily conducted on mice, but the researchers also did tests that showed the same genetic processes happen in human brains.
While scientists have already found genes that are connected to dementia, it has not yet been determined how those genes impact the disease’s progression. But in this study, researchers analyzed the genetic processes that cause tau to produce clumps in the brain, harm nerve cells and eventually, contribute to dementia.
The researchers focused on mice with symptoms of frontotemporal dementia — a form of early-onset dementia — because the processes that lead to a build-up of tau in the brain resemble what is thought to take place in the brains of those with Alzheimer’s disease.
“Our study is the most comprehensive effort to date to identify the source of neurodegeneration across species and provides an important roadmap for the development of potentially effective new drugs for Alzheimer’s disease and other dementia,” said lead author Dr. Daniel Geschwind, a professor of neurology and psychiatry at UCLA.
Unlike previous studies that have only looked at one inbred mouse strain, something Geschwind’s team believes makes it difficult to connect findings to humans, the researchers looked at three strains of mice with genetic variations.
The researchers identified two gene clusters that cause tau to accumulate in the brain, leading to cell death, in all three strains of mice. Their analysis revealed that the same processes also take place in human brains.
Although drug companies have spent billions trying to target beta-amyloid, another toxic protein that is found in the brains of those with Alzheimer’s disease, these findings support previous studies that suggest targeting tau could help prevent the brain from deteriorating and developing dementia.
“It seems that in Alzheimer’s disease, amyloid accumulation in the brain starts first, but symptoms typically occur after the amyloid pathology induces the tau pathology, at which point neuronal cell death and the loss of synapses start to accelerate,” said Henri Huttunen, an instructor at the Neuroscience Center of the University of Helsinki, about a previous study that focused on the formation of Alzheimer’s disease.
The UCLA-led research team is the first to find two gene clusters that may lead to neurodegeneration. After their discovery, they searched a large database of the genetic effects of experimental drugs to find drugs that could decrease cell death. They tested the drugs on human cell cultures and found that they helped prevent neurodegeneration, an intervention that could potentially change the course of a disease like Alzheimer’s.
“There is still a significant amount of work that needs to be done to develop drugs that could be effectively used in humans against these targets, but this is an encouraging step,” said Geschwind.