Researchers have opened a new window into understanding and possibly interrupting the progression of Alzheimer’s disease using an approach that is also yielding insights into cancer and other diseases. St. Jude Children’s Research Hospital scientists led the study, which appears today in the journal Neuron.
The approach involved tracking changes in expression of most proteins in the frontal cortex, the brain region decimated by Alzheimer’s disease. Because proteins function in networks, researchers also traced the networks involved. The goal was to better understand how the brain changes as the disease progresses.
Altered expression of 173 proteins working in 17 pathways was associated with disease progression, researchers reported. In some cases, protein expression was upregulated (increased) and in others downregulated (decreased). The association was validated in two independent groups of adults with Alzheimer’s disease as well as in a mouse model. Only about 20% of the 173 proteins had previously been strongly linked to the neurodegenerative disease.
“Alzheimer’s disease is the most common cause of dementia, yet these results show we only understand the tip of the iceberg in terms of disease mechanisms, which slows development of novel treatments,” said co-corresponding author Junmin Peng, Ph.D., of the Departments of Structural Biology and Developmental Neurobiology. Peng also directs the Center for Proteomics and Metabolomics at St. Jude. The co-corresponding and co-first author is Xusheng Wang, Ph.D., of the University of North Dakota and formerly of St. Jude.
The study was the most comprehensive look yet at protein expression in brain tissue. About 150 adults at different stages of Alzheimer’s disease and control samples were included in the study. The tissue samples were from the Banner Sun Health Research Institute and the Icahn School of Medicine at Mount Sinai. The control samples included adults without Alzheimer’s disease and those with a different neurodegenerative disorder.
More than 14,500 proteins were profiled. The project required cutting-edge technology, sophisticated analytic tools and a pipeline for analyzing and prioritizing the results. “We are applying the approach to other diseases, including cancer and immune disorders,” Peng said.
Researchers integrated the proteomic and next-generation sequencing data to identify proteins and pathways as research priorities. The list included those associated with inflammation, accumulation of the disease-associated molecules-amyloid-beta and tau, development, lipid metabolism, iron balance and others.
“Some of the changes in protein expression identified in this study will turn out to cause the disease,” Peng said. “Those will aid in designing novel diagnostic and treatment strategies.”
For example, further comparisons of protein expression in brain tissue and the cerebrospinal fluid revealed possible biomarkers that could yield new diagnostic tests or ways to track disease progression or treatment response.
Researchers also compared the human and mouse proteomes and identified differences that might help explain why experimental treatments that work well in mice fail in humans. The proteome is the complete set of proteins that are or can be expressed in a given cell at a given time.
The other first authors are Bing Bai, Ph.D., formerly of St. Jude; and Yuxin Li, Ph.D., and Ping-Chung Chen, Ph.D., of St. Jude. The other authors are Kaiwen Yu, Kaushik Kumar Dey, Jay Yarbro, Xian Han, Brianna Lutz, Shuquan Rao, Yun Jiao, Jeffrey Sifford, Haiyan Tan, Timothy Shaw, Ji-Hoon Cho, Suiping Zhou, Hong Wang, Mingming Niu, Ariana Mancieri, Kaitlynn Messler, Xiaojun Sun, Zhiping Wu, Vishwajeeth Pagala, Anthony High, Wenjian Bi, Hui Zhang and Hongbo Chi, all of St. Jude; Jonghee Han and Gang Yu of the University of Texas Southwestern Medical Center; Minghui Wang, Vahram Haroutunian and Bin Zhang, all of the Icahn School of Medicine at Mount Sinai; and Thomas Beach of Banner Sun Health Research Institute.
The research was funded in part by grants (AG047928, AG053987, GM114260, AG064909, AG057440, NS079796, NS072026, AG19610, CA021765) from the National Institutes of Health; contracts with the Arizona Department of Health Services and Arizona Biomedical Research Commission; and ALSAC, the St. Jude fundraising and awareness organization.