ST. LOUIS — Alzheimer’s disease affects an estimated 6.9 million Americans, and yet there is no way to study this disease in research labs — making discovering treatment options nearly impossible.
Until now.
Washington University researchers have discovered a way to simulate Alzheimer’s progression outside of a living patient, so it can be studied accurately in a lab. The advancement will likely simplify and accelerate the development of ways to treat or even prevent the disease.
The findings were published Thursday in the journal Science.
“There are millions of patients experiencing Alzheimer’s disease, and for the late-onset type that 95% of patients experience, there has been no valid human model,” said Zhao Sun, a staff scientist at Washington University and first author of this study. “Now, we can devise a patient-specific model — in a dish.”
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Alzheimer’s disease affects neurons, our brains’ communication cells. And all the neurons that are grown in labs are young — making them far from ideal for studying an age-dependent disease, unless you can wait 60 years for them to grow old enough to get sick.
The Washington U scientists have effectively asked: How can we mimic Alzheimer’s progression outside of a patient — in a petri dish, or a beaker — so we can poke and prod it until we figure out a way to stop it?
This sort of thinking will be especially helpful for the kind of Alzheimer’s that effects 95% of patients: age-dependent, or sporadic, Alzheimer’s.
The disease lives up to both of its names, as symptoms ramp up as patients get older, and its origins are highly complex and poorly understood.
Scientists think the roots of age-dependent Alzheimer’s may lie in the intersection of patients’ genes, lifestyles and environments — which has made it hard to replicate for studies in highly controlled lab environments.
The age component to this disease, however, has been even harder for scientists to address in research.
And although there were ways to make Alzheimer’s-like neurons grow in labs, precisely re-creating the way the disease progresses in people — over time, with age — is critical for coming up with drugs that are much more likely to succeed in clinical trials in mice, and afterward in humans.
This is where the Washington University study comes in. The goal was to generate neurons in a lab that are the same age as the patients experiencing disease, authors said.
They found a way to create neurons that “act their age” in the lab.
Since neurons can’t be safely removed from patients with Alzheimer’s — or any patients, for that matter — most researchers take cells that are easier to collect, like skin cells, and transform them into neurons.
The Washington University researchers use a unique blend of cellular machinery to make this switch without erasing the age of the cells taken from patients.
“We have a bit of a different angle thinking about cell fate,” said Andrew Yoo, Washington University professor of developmental biology and senior author of the paper.
The researchers performed a series of tests to see how similarly these lab-grown neurons behaved to those in people with age-dependent Alzheimer’s disease.
The lab neurons passed every test. They formed troublesome protein complexes that normally interfere with Alzheimer’s patients’ brain function. They deteriorated quickly over time.
This system is the first of its kind that will allow scientists to accurately study aging brains without having to wait until it’s too late.
“When patients pass away, their families can donate their brains to science and we can study them that way, but other than that, there is no technology now to study live 3-D brain functions,” Dr. William Maurice Redden, a geriatric psychiatrist at Saint Louis University said.
The new study will change that by providing a human-cell system for understanding disease progression and testing potential therapeutics.
According to Redden, there are very limited treatment options for Alzheimer’s, and none that restore cognitive function lost as patients’ neurons deteriorate.
The new model for Alzheimer’s has already proven useful for identifying possible genetic culprits for the age-dependent version of the disease, according to Yoo.
“We were trying to figure out what would make neurons angry throughout aging,” Sun said. The neurons in this study showed signs of inflammation, which is common in the brains of Alzheimer’s patients, but not something that scientists thought neurons could initiate on their own.
Sun said it has always been thought that inflammation in patients came from neurons interacting with the immune system, but it turns out neurons can initiate the inflammation process all on their own.
The researchers wanted to know how these neurons were initiating inflammation. “Transposable elements,” small segments of DNA that can essentially copy-and-paste themselves around our genome whenever and wherever they want to (even when they get in the way of important genes), have been shown to play a role in inflammation in the past. So, this was the pathway the authors decided to investigate further.
“Throughout aging, everyone goes through changes in their transposable elements, but what’s important here is that the healthy neurons can cope with these changes,” Yoo said. “The Alzheimer’s neurons have a harder time dealing with these changes.”