Yale Daily News

Pioneering Alzheimer’s research conducted at Yale-NUS — which tested a metabolic stimulant on invertebrates — may shift how scientists approach aging and age-dependent diseases.

Earlier this month, Jan Gruber, an assistant professor of biochemistry at Yale-NUS, published the team’s research on the disease in eLife, a scientific journal. Gruber — the study’s principal investigator — and a cohort of professors and students experimented on worms. The scientists genetically modified the test subjects so that their neurons produced plaque that also exists in the brains of Alzheimer’s patients. Gruber and his team believe that their research will necessitate a paradigm shift in how scholars approach Alzheimer’s and other similar diseases.

“I view age-dependent diseases [including Alzheimer’s disease] as manifestations of ageing,” Gruber wrote in an email to the News. “So I consider this work an extension (and part) of our research on ageing. The idea is to prevent or delay age-dependent diseases by targeting fundamental mechanisms of ageing.”

Gruber’s experiment exposed the genetically modified worms to metformin — a drug that makes the body think it is becoming malnourished, forcing the subject to care for itself more intensively. Upon exposure to metformin, the worms overcame their symptoms of Alzheimer’s and outlived worms lacking the neurons with plaque. He wrote in an email to the News that his team hopes to use their experimental model “to explore mechanisms of ageing, test/develop interventions and preventative treatments.”

The paper was a collaborative effort between faculty from the National University of Singapore and Duke-NUS, but most of the project took place in Gruber’s lab at Yale-NUS. Gruber’s team also included a Yale-NUS undergraduate.

As Gruber told The Straits Times, a sparse amount of research tackles Alzheimer’s disease itself, choosing instead to focus inquiries on drugs designed to combat its symptoms. In an email to the News, Gruber said his research on Alzheimer’s required his team to “work backwards” in observing the aging process. He added that with his team, he identified “profound mitochondrial defects” early on in the lifespan of the invertebrates.

Gruber’s lab is working on a variety of small projects that expand upon the research published in eLife. His goal is to further investigate the relationship between aging and age-dependent diseases such as Alzheimer’s. Pending funding and collaborative efforts with Singapore’s National University Health System Centre for Healthy Ageing, Gruber hopes to research “the link between molecular mechanisms of ageing and neuro-degenerative diseases.”

Vice President and Vice Provost for Global Strategy Pericles Lewis, who served as Yale-NUS’ inaugural President from 2012 to 2017, described Gruber as “an outstanding young biologist.”

“Like many of the Yale-NUS STEM faculty, he has a research lab that is provided by Yale-NUS but works closely with other departments at the National University of Singapore, which is a science powerhouse,” Lewis wrote in an email to the News. “Yale-NUS has been able to support excellent science research through partnerships like this, and the young scientists there are doing very interesting work while also helping Yale-NUS undergraduates gain exposure to cutting-edge research techniques.”

Yale maintains its own Alzheimer’s Disease Research Center in New Haven under the School of Medicine’s Neurology Department. Neurology and Neuroscience professor Christopher van Dyck co-leads the research center, and emphasized the need for preclinical research on the disease.

“I think this kind of method, using a preclinical model, allows us to screen therapeutics on molecular level very rapidly. The limitations, of course, would be that all preclinical models so far have failed to fully simulate human Alzheimer’s disease,” van Dyck said in an interview with the News. “The therapeutic they tested, metformin, has been tested on humans, disappointingly. However, we do badly need preclinical models for at least basic molecular mechanisms relating to Alzheimer’s.”

Yale-NUS was founded in 2011.