Untangling neurodegenerative complexity through collaboration
In her lab at the University of Otago, Brain Research New Zealand (BRNZ) Principal Investigator, Associate Professor Ping Liu, asks some big questions. Using a host of different techniques, she is exploring the neurobiology of age-related cognitive decline, Alzheimer’s disease and schizophrenia. And she’s untangling some of the complex biological mechanisms that shape learning and memory. What unifies her research is the identification and validation of biomarkers – chemical clues in the blood, brain or cerebrospinal fluid (CSF) that can be used to detect neurological disorders, long before any symptoms appear.
Some of those biomarkers are produced via a highly-versatile amino acid called arginine, present in almost every cell in the body. But as Liu explains, what really makes arginine so interesting is the products it can metabolise into; a wide variety of bioactive molecules that help maintain normal cell function. “For example, some of its metabolites are critical for neurotransmission and cerebral blood flow, so if levels are off, things can go wrong,” she says. Since completing her PhD with Professor David Bilkey in 1998, Liu has gone on to establish much of our current understanding of arginine metabolism and its implications for the human brain.
Liu says that her research is motivated by her former career as a medical doctor. While working in geriatrics at China’s Anhui Provincial Hospital, Liu met lots of patients with Alzheimer’s disease, but that, without a good way of assessing and treating them, “once patients got to the ward, they ended up staying there,” she says. By working to better understand the progression of the disease, Liu hopes to be able to diagnose it much earlier, and improve the outcomes for those who live with it.
Key to Liu’s success has been her flexibility, “In the past, people focused on a single pathway. Because arginine can be metabolised by multiple enzymes, there are multiple pathways that should be investigated.” Much of Liu’s research looks at the pathways that produce three main metabolites – nitric oxide, agmatine and polyamines – all of which could have implications for the detection and treatment of neurodegenerative and psychiatric disorders.
For example, in her rodent models, Liu has shown that agmatine not only directly participates in normal learning and memory processes, but it may also have a therapeutic effect in cases of cognitive impairment. She has also connected the excessively low production of nitric oxide to the progression of dementia, and shown that polyamines may have an important role in combating amyloid and tau pathology, the hallmarks of Alzheimer's.
Liu is currently collaborating with two neurologists in Spain on a large BRNZ-funded Alzheimer’s biomarkers project. The team also includes Professor Paul Smith and Associate Professor Lynette Tippett. By looking at human blood and CSF samples, Liu and her colleagues are aiming to explore and validate the use of arginine-based biomarkers for the diagnosis of Alzheimer’s disease. According to Liu, “These samples are incredibly precious. They allow us to identify specific metabolites linked to mild cognitive impairment and Alzheimer’s. They may also help us to better predict to conversion between those two conditions”. While the work on the Spanish blood and CSF samples is ongoing, preliminary results are interesting, and Liu says, they plan to “…. further validate the identified plasma biomarkers using samples obtained from BRNZ’s Dementia Prevention Research Clinics”.
All of this work has contributed a growing body of evidence from labs across the world. Liu has extended her arginine research to other neurodegenerative diseases such as Parkinson’s disease and frontotemporal dementia, and to psychiatric disorders including schizophrenia and depression. Ultimately, her research suggests that various changes in arginine metabolism could signal the progression of a large number of neurodegenerative diseases and psychiatric disorders.
Liu’s latest project – a new collaboration with Professor Jijun Wang at Shanghai Mental Health Centre – will allow her to extend these ideas even further. Liu met Prof Wang through her connection with BRNZ. She says, “Last year, (BRNZ Co-Directors) Peter and Cliff organised a research forum with their Chinese counterparts. I was one of the delegates who travelled to Shanghai. I presented various aspects of my biomarkers research to Prof Wang and his colleagues, and they were very, very interested.” And now, through a Memorandum of Understanding between the University of Otago, Enterprise Dunedin, and the Shanghai Science and Technology Commission, Liu has been awarded a research grant to work directly with Prof Wang.
“Prof Wang is leading an internationally-recognised large cohort study of adolescents and young adults at high-risk for psychosis. Shanghai Mental Health Centre also has over 600 beds for Alzheimer’s disease patients,” Liu says. “Our research is very complementary, and I believe there’ll be some interesting and fruitful outcomes to our collaboration.” In the next few months, Liu will visit Shanghai again, this time to discuss the setup of her unique research methods in Prof Wang’s lab. For Liu, this collaboration is an exciting one, “In order to validate our biomarkers, we need to do truly large-scale clinical research. Working with Jijun will give us that opportunity. I’m very happy to be collaborating with him.”