A research team from the IU School of Medicine made a significant discovery in 2022 at the Stark Neurosciences Research Institute, revealing a novel gene mutation in the brain associated with variations in Alzheimer's disease risk.
Alzheimer's disease is a progressive brain disorder causing memory loss and cognitive impairment, often in older individuals. In fact, according to BrightFocus, more than 33% of people over the age of 85 are diagnosed with the disease. It results from abnormal protein buildup in the brain, leading to cell damage and death. Common symptoms include confusion, mood changes and difficulty with daily tasks. Although there is no cure, treatments aim to alleviate symptoms and slow the disease's progression. Ongoing research strives to uncover its causes and develop more effective therapies.
The project was spearheaded by a graduate student named Andy Tsai, supervised by Martin Professor of Alzheimer’s Research, Gary Landreth, and executive director of Stark Institute, Bruce Lamb.
Since 2017, the Stark Neurosciences Research Institute has been working to uncover the basis for Alzheimer’s disease. Around this time, Tsai said he was enamored with the concept of human pathways in the brain potentially harboring something that could affect the onset of Alzheimer’s disease and perused an array of scholarly papers on the topic.
Tsai’s deliberations were centered around the phospholipase C gamma 2 (PLCG2) gene in the microglia. The microglia is known to be the first line of defense against any malicious diseases within the brain. The decay of brain activity is associated with the deposition of amyloid plaque in the microglia. This consequently limits how the brain learns and forms new memories. Prior to the study, there was a paper published in 2017 that identified a PLCG2 variant called P522R, which was found to protect against Alzheimer’s disease.
Tsai said he approached his mentors Landreth and Lamb with the hypothesis that there could be a mutation like P522R that did the exact opposite function, instead elevating the risk of Alzheimer’s.
Tsai said that Landreth originally told him his hypothesis would fail.
“He thought the test subjects would not reflect any observable activity since it was just one mutation that was too subtle,” Tsai said.
While conducting research, his team associated the M28L variant of PLCG2 with Alzheimer’s disease.
“In the end, I was glad to prove him wrong,” Tsai said.
Geneticists at the MODEL-AD consortium at Stark Institute scanned and identified the PLCG2 gene and injected its protective P522R mutation into a mouse that was subsequently sent to Indianapolis, he said. The team started conducting research in January 2018 and has been working on this project ever since.
Tsai said he devoted around twelve hours every day in the lab, with his sole companions being the mice he was experimenting on.
“It was difficult for me because my mother was very sick at the time and eventually passed away in 2018,” Tsai said. “Before she passed away, she said, ‘You can’t save me, but try your best to save others’ and this encouraged me to find a way to help others’ parents suffer less.”
Tsai said he dissected the functions of the microglia in the mice and identified new therapeutic targets. He observed the risk variant within the mice test subjects ignored the amyloid plaque in the microglia whereas the protective variant showed an enhanced immuno-response to protect the neurons and lumped together with the plaque deposits, eliminating it from the brain. Landreth said the impact of their research isn’t well known in the medical world.
“What we really showed was that we can bidirectionally change and control the risk of Alzheimer’s,” Landreth said. “This is emblematic to identifying which genes to further target and develop drugs.”
He said this collaboration could have only been achieved at Stark Neuroscience Research Institute because of its resources and experienced researchers available to tackle such problems. They have published the paper in the journal Immunity.
TREAT-AD, another consortium within Stark Neuroscience Research Institute, started developing experimental drugs to test the findings of Tsai’s research, Landreth said. Last week, a formative drug was administered to a patient at IU Health, which demonstrated a moderate degree of efficacy in reducing the amyloid plaque and hindering the progression of the disease.
The team is excited about the progress, and they hope to develop future iterations of the drug and effectively change the trajectory of the disease.
Stephanie Bissel, the associate professor of radiology and imaging sciences, said Tsai is succeeded by PhD students, Evan Messenger and Logan Bedford.
“Our hypothesis has been on target, and we are eager to start dissecting more pathways,” she said. This can open new doors in the study of Alzheimer’s disease that haven’t been explored thus far.”
