ASU/TGen-led study identifies source of mutation in Alzheimer’s disease

ANK1 gene expression change found in brain's microglia cells associated with neuroinflammation


July 12, 2017

Researchers led by Arizona State University and the Translational Genomics Research Institute (TGen) have identified altered expression of a gene called ANK1, which only recently has been associated with memory-robbing Alzheimer’s disease, in specific cells in the brain.

Using an extremely precise method of isolating cells called “laser capture microdissection,” researchers looked at three specific cell types — microglia, astrocytes and neurons — in the brain tissue of individuals with a pathological diagnosis of Alzheimer’s disease, and compared them with brain samples from healthy individuals and those with Parkinson’s disease. Diego Mastroeni, an assistant research professor at Biodesign’s ASU-Banner Neurodegenerative Disease Research Center, and the study’s lead author. Download Full Image

Following sequencing of each of these cell types, the ASU/TGen-led team found that altered ANK1 expression originates in microglia, a type of immune cell found in the brain and central nervous system, according to the study published today in the scientific journal PLOS ONE.

“Although previous genetic and epigenetic-wide association studies had shown a significant association between ANK1 and AD, they were unable to identify the class of cells that may be responsible for such association because of the use of brain homogenates. Here, we provide evidence that microglia are the source of the previously observed differential expression patterns in the ANK1 gene in Alzheimer’s disease,” said Diego Mastroeni, an assistant research professor at Biodesign’s ASU-Banner Neurodegenerative Disease Research Center, and the study’s lead author.  

All three of the cell types in this study were derived from the hippocampus, a small looping structure shaped like a seahorse (its name derives from the Greek words for horse and sea monster). The hippocampus resides deep inside the human brain and plays important roles in the consolidation of both short- and long-term memory, and in the spatial memory that enables the body to navigate.

In Alzheimer's disease — and other forms of dementia — the hippocampus is one of the first regions of the brain to suffer damage, resulting in short-term memory loss and disorientation. Individuals with extensive damage to the hippocampus are unable to form and retain new memories.

“Using our unique data set, we show that in the hippocampus, ANK1 is significantly increased four-fold in Alzheimer’s disease microglia, but not in neurons or astrocytes from the same individuals,” said Winnie Liang, an assistant professor, director of TGen Scientific Operations and director of TGen’s Collaborative Sequencing Center. “These findings emphasize that expression analysis of defined classes of cells is required to understand what genes and pathways are dysregulated in Alzheimer’s.”

Alzheimer’s features many signs of chronic inflammation, and microglia are key regulators of the inflammatory cascade, proposed as an early event in the development of Alzheimer’s, the study said.

Because the study found that ANK1 also was increased two-fold in Parkinson’s disease, “these data suggest that alterations in ANK1, at least in microglia, may not be disease-specific, but rather a response, or phenotype associated with neurodegeneration … more specifically, neuroinflammation.”

More than 5 million Americans have Alzheimer’s, an irreversible and progressive brain disorder that slowly destroys memory, thinking skills and eventually the ability to conduct even the simplest of tasks. For most patients, symptoms first appear in the mid-60s. For older Americans, it is the third-leading cause of death, following heart disease and cancer, according to the National Institutes of Health.

“The success of this, and many other studies, owes a great deal to the support and collaborative nature of the people of the Arizona Alzheimer’s Consortium. The results obtained in this work emphasize the importance of methods that enable us to characterize the molecular profile of defined cells, either as a group or as single cells, that have been defined by any of several means,” said Paul Coleman, research professor at Biodesign’s ASU-Banner Neurodegenerative Disease Research Center, and the study’s senior author.

Eric Reiman, director of the Arizona Alzheimer's Consortium and Clinical Director of Neurogenomics at TGen, said: “This study demonstrates the value of bringing together talented researchers from different disciplines and organizations to advance the scientific fight against Alzheimer’s disease.”

Also contributing to this study were: Banner Sun Health Research Institute; University of Exeter Medical School; and the Institute of Psychiatry, Psychology and Neuroscience at King’s College London.

The study — ANK1 is up-regulated in Laser Captured Microglia in Alzheimer’s brain; the importance of addressing cellular heterogeneity — was funded by the Arizona Biomedical Research Commission, and the Arizona Alzheimer’s Consortium. The consortium’s annual scientific symposium was May 18 at Mayo Clinic Hospital in Phoenix, where the authors presented details of these findings.  

Media contact: Joe Caspermeyer, 480-727-9577, Joseph.Caspermeyer@asu.edu

ASU professor helps students learn, lead and innovate


July 13, 2017

Mike Tueller has many talents. He completed an academic conference paper in high school, served in the U.S. Navy and studied at Harvard University. He also landed his childhood dream job: professor.

“Of course, there’s no way I could have known as a preschooler what a university professor really did,” said Tueller, associate professor of ancient Greek in the School of International Letters and Cultures at Arizona State University. “So, I have to consider it the sheerest luck that I’ve actually found this job suits me.” Mike Tueller, associate professor of ancient Greek Mike Tueller is an associate professor of ancient Greek in the School of International Letters and Cultures, an academic unit in the College of Liberal Arts and Sciences at Arizona State University. Download Full Image

Tueller started programming computers for a research project at a local university while in high school. The project’s aim was to develop high-powered space-based lasers as part of former President Ronald Reagan’s Strategic Defense Initiative, more commonly known as the “Star Wars Defense” plan. 

“I’ll admit this may sound more impressive than it is, but you should remember it was the '80s. A university research project couldn’t have a grad student do the work because the only people who knew how to program computers were high-schoolers,” he said. “But this means I delivered my first academic conference paper when I was 17, and in a completely different field from the one I find myself in now.”

As an undergraduate at Harvard University, Tueller first majored in astrophysics for his love of science. He said he hadn’t heard of the Classics as an academic field until he met one of his roommates. He switched his major to Classics and received his bachelor’s degree in 1992.

“I still love science, but I really wanted to try something different,” Tueller said. “And, like a lot of people who make similar switches, I was hooked.”

Tueller took a Navy Reserve Officers' Training Corps scholarship at Harvard. He served as an officer in the U.S. Navy for four years in between his undergraduate and graduate years, most of which was spent in Puerto Rico. In 2003, he completed his doctoral program in classical philology at Harvard. He taught for five years at Brigham Young University before joining the faculty at ASU in 2008.

Tueller teaches courses in ancient Greek language and literature. His research focuses on Greek epigrams, which began as inscriptions on objects but soon turned into very short, ancient poems that often feature witty turns of phrase or thought. He is currently re-editing the Loeb Classical Library’s standard English edition of “The Greek Anthology,” an ancient collection of about 4,500 short poems.

“These poems are tricky: they’re so short that they omit all context. In fact, they make a game out of forcing the reader to guess what their original context would have been,” Tueller said. “In my research, I have attempted to determine how ancient readers would have processed these poems – from discovering the reader’s starting point to how the nuance of individual words would play out across the poem, and where the surprises lie.”

Tueller said many people criticize forms of speech that are known for being short, such as the “tweet” or “sound bite,” because they believe it’s a diminution of public discourse. Tueller disagrees with this opinion, saying brevity is suitable for some kinds of expression.

“I think the Greek epigram can give us an example of how a rich literary tradition adapted to circumstances that favored brevity,” Tueller said. “Every new thing I discover in my research, no matter how small, feels like a jolt of electricity. And in my teaching, I get to see students have that same experience — a sudden flash of insight can redirect a life.”

While many students come to professors with very specific job-related worries, Tueller said it’s our responsibility as a university to raise their sights beyond the workforce.

“An undergraduate education should give its graduates the skills not just to do what they’re told but to forge their own paths, to innovate and to lead,” Tueller said. “This requires a much broader education in the world and its ways, and the cultivation of some very hard-to-pin-down skills in incisive observation and critical analysis without boundaries.”

Tueller teaches in a field with a long tradition of paying very close attention to words. He said a student who has acquired a precise ability to question the meaning behind words is less likely to be deceived and more likely able to address any need. Further, rigorous habits of reading, writing and speaking make clearer thinkers and more effective leaders.   

“Learning involves a leap into the unknown,” Tueller said. “You have to take the risk of being wrong and looking foolish if you’re ever going to make any progress.”

Amanda Stoneman

Copywriter, College of Liberal Arts and Sciences