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Preview of the Possible

Unprecedented neuronal models advance Alzheimer’s and autism research

With good reason, the human brain is called the most complex object in the known universe. Aside from its billions of neurons and trillions of connections and the mind-bending notion that it’s an object seeking to comprehend itself, there’s the fact that the human brain almost never gives up its secrets easily.

Nowhere is that more painfully evident than in the cases of Alzheimer’s disease (AD) and autism, two distinctly different neurological disorders that share the confounding trait of being extraordinarily difficult to study — let alone diagnose or treat.

Alzheimer’s disease, for example, is nearly impossible to diagnose before symptoms appear late in life. By then, said Larry Goldstein, PhD, professor in the UCSD Departments of Cellular and Molecular Medicine and Neurosciences, abnormal or dying brain cells have accumulated years, even decades, of damage.

Autism, on the other hand, strikes early, but no less mysteriously. Toddlers who were on a seemingly normal course of development suddenly display neurological and behavioral symptoms of the disease, from diminished or lost communication skills to obsessivecompulsive behaviors.

To find a cure for these disorders — none currently exists for either — scientists must unravel what’s happening to an afflicted brain at the cellular and molecular level. Until quite recently, that’s been basically impossible.

“We’re dealing with the human brain. You can’t just do a biopsy on living patients,” said Goldstein, who also directs the UC San Diego Stem Cell Program and is scientific director of the Sanford Consortium for Regenerative Medicine, which is comprised of five San Diego-based research institutions. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or by using limited animal models. Neither approach is really satisfactory.”

Alysson Muotri, PhD

"We can now look for and test drugs and therapies and see what happens at a cellular and molecular leve."
- Alysson R. Muotri, PhD

Last year, though, Goldstein and colleagues announced a potentially profound advance in AD research: They created stem cell-derived in vitro models of both hereditary and sporadic AD neurons.

“Creating highly purified and functional human Alzheimer’s neurons in a dish — this has never been done before,” Goldstein said. “These aren’t perfect models. They’re proof of concept. But now we know how to make them.”

More importantly, the stem cell-derived AD neurons present the possibility of not just examining their cellular biology, but using them to directly test new therapies. Currently, no drugs exist that can change the course of the disease.

“At the end of the day, we need to use cells like these to better understand Alzheimer’s and find drugs to treat it,” Goldstein said. “We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us — emotionally and financially.”

About Alzheimer’s and Autism

More than 30 million people worldwide (almost 6 million in the U.S.) are afflicted with Alzheimer’s, a devastating degenerative disease that eats away at cognitive functions, such as memory. It’s harder to know how many people suffer from autism spectrum disorder, partly because it encompasses a wide range of conditions and partly because recordkeeping varies by country. In the United States, the Centers for Disease Control and Prevention estimates roughly 1 million American children have diagnosed autism spectrum disorder. The worldwide number, including diagnosed and undiagnosed, is likely in the tens of millions.

Larry Goldstein, PhD

Larry Goldstein, PhD

Goldstein and colleagues created “Alzheimer’s in a dish” by extracting fibroblasts (a kind of skin cell) from patients with heritable familial AD and with sporadic AD — the latter of which is more common but its cause unknown. The fibroblasts were then reprogrammed into induced pluripotent stem cells (iPSCs) that could be differentiated into working neurons that display biochemical indicators of AD.

Alysson R. Muotri, PhD, assistant professor of pediatrics and cellular and molecular medicine, and colleagues did something similar in 2010 when they used iPSCs from patients with Rett syndrome to create the first functional human cellular model for studying the development of autism spectrum disorder.

“This work is important because it puts us in a translational mode,” Muotri said. “It helps expand and deepen our understanding of autism, from a behavioral disorder to a developmental brain disorder. We can now look for and test drugs and therapies and see what happens at a cellular and molecular level. We will learn what kind of drugs work in what types of autism. That’s something we’ve never been able to do before.”

Rett syndrome (RTT) is a neurological disorder in which affected children display normal development until the age of six to 18 months, after which physical and behavioral symptoms begin to emerge, from low muscle tone and progressive motor dysfunction to diminished or disappearing socialization abilities. It is one of the most aggressive forms of autism.

Sanford Consortium for Regenerative Medicine

The Sanford Consortium for Regenerative Medicine

RTT is caused by mutations to a gene that encodes for a protein implicated in other types of psychiatric disorders. Affected neurons have fewer synapses, reduced spine density and signaling defects. In other words, they don’t work very well.

In a preview of the possible, Muotri’s research showed how iPSCs might offer a future human treatment. He exposed his newly created human RTT- iPSCs to a protein growth factor called IGF-1, which has shown some beneficial effects in mouse models. The protein appeared to rescue some RTT- iPSCs, clearing away some neuronal defects, though researchers don’t yet understand exactly how it happens. IGF-1 is currently in clinical trials for patients with RTT.

“This suggests that the synaptic deficiencies of Rett syndrome, and likely other autism spectrum disorders, may not be permanent,” he said.

In other words, it might be possible to develop drugs that halt and reverse neuronal deficiencies in autism, Alzheimer’s and other degenerative neurological conditions. That achievement is a long way off, of course, but the creation of these induced, impaired neurons marks a big step in that direction.