The University of California, Irvine has been awarded a five-year, $14 million grant from the National Institutes of Health to study brain circuits that are susceptible to aging and Alzheimer’s disease. The research findings will advance the development of early diagnostic tools and the discovery of new treatment strategies.
Xiangmin Xu, Ph.D., UCI Chancellor’s Fellow of anatomy and neurobiology and principal investigator, will lead an interdisciplinary, multi-institutional team whose goal is to construct comprehensive, high-resolution maps of specific neuron types and their connections in critical brain circuits whose defects correspond with behavioral deficits associated with aging and Alzheimer’s disease.
“One of the early warning signs of Alzheimer’s disease is increasing forgetfulness which is a sign of disrupted learning and memory processes in a part of the brain called the hippocampus. Our guiding hypothesis is that age- and Alzheimer’s disease-related pathologies cause selective changes to cell-type-specific hippocampal formation hubs, ultimately leading to cognitive deficiencies,” said Xu, who is also director of the Center for Neural Circuit Mapping.
“We will perform large-scale, cell-type-specific mapping of the hippocampus, subiculum and entorhinal complex, which show the earliest signs of neurodegeneration, and are also connected with many critical brain regions. Analysis of the cellular resolution neural connection data generated, which includes molecular and anatomical annotations, will identify vulnerable subcircuits, greatly increasing our understanding of the specific brain circuits that are most at risk for Alzheimer’s disease.”
Leveraging the exceptional resources of the UCI CNCM, Model Organism Development & Evaluation for Late-Onset Alzheimer’s Disease Consortium funded by the National Institute on Aging of the National Institutes of Health, and the Allen Institute for Brain Science, the team will produce important standardized and comprehensive reference atlases, enabling data and resource sharing for the Alzheimer’s disease research community.
“What is exciting about our work is that we will identify new early warning signs and novel treatment strategies for Alzheimer’s disease when the disease is still potentially treatable,” Xu said. “Our work illustrates the power of building a scientific dream team. No single lab could possibly attempt to carry out what we will do.”
The project team members are co-PI Kim Green, Ph.D., professor of neurobiology & behavior; co-investigators Todd C. Holmes, Ph.D., professor of physiology & biophysics; Grant MacGregor, D.Phil., professor id development & cell biology; Albert La Spada, M.D., Ph.D., professor of pathology & laboratory science; and Gopi Meenakshisundaram, Ph.D., professor of computer science; all from UCI; co-PIs Eran A. Mukamel, Ph.D., UCSD associate professor of cognitive science; and Wei Xu, Ph.D., assistant professor of neuroscience, UT Southwestern Medical Center in Dallas. The team also includes two members from the Allen Institute for Brain Science in Seattle: co-investigator Lydia Ng, Ph.D., and collaborator Hongkui Zeng, Ph.D., executive vice president and institute director.
UCI is a platinum-level Leaders Circle partner of the Greater Irvine Chamber.
Photo by Steve Zylius / UCI: “This project will capture a composite of disease features to expand our understanding of the brain circuits susceptible to aging and Alzheimer’s. Our findings will facilitate the development of more effective early diagnostic tools and the discovery of new therapies,” says UCI’s Xiangmin Xu.