Scientists at St. Jude Children’s Research Hospital demonstrated for the first time that the protein midkine plays a preventative role against Alzheimer’s disease. Midkine is known to accumulate in Alzheimer’s disease patients. Now, researchers have connected it with amyloid beta, a protein that accumulates in the brain, causing assemblies that are a hallmark of Alzheimer’s.
In work published on August 21 in Nature Structural & Molecular Biology, the researchers revealed that midkine prevents amyloid beta from sticking together, and, consequently, Alzheimer’s disease models lacking midkine show more amyloid beta accumulation. The findings lay the groundwork to better understand the disease-preventing mechanism of midkine and subsequent drug discovery pathways.
Midkine blocks Alzheimer’s amyloid assembly growth
Midkine is a small, multifunctional growth factor protein found abundantly during embryonic development but also involved in normal cell growth. Its role in cell growth means that midkine is often overexpressed in cancer, making it a valuable biomarker. However, beyond some preliminary studies showing its increase in Alzheimer’s, midkine’s link to the neurodegenerative disease has been poorly understood.
Corresponding author Junmin Peng, PhD, Departments of Structural Biology and Developmental Neurobiology, and his team utilized fluorescence assays, circular dichroism, electron microscopy and nuclear magnetic resonance with disease models that replicate amyloid beta accumulation to investigate the role of midkine in Alzheimer’s thoroughly. They found that midkine and amyloid beta have a similar pattern at the protein level.
“We know that correlation is not causative, so we wanted to demonstrate convincingly that real interactions are occurring between the two proteins,” Peng explained.
The researchers used a fluorescent sensor for amyloid beta assemblies, called thioflavin T, to show that the assemblies were broken up in the presence of midkine. Modeling of those data revealed that midkine inhibits amyloid beta elongation and secondary nucleation, two specific phases during assembly formation. Nuclear magnetic resonance confirmed this finding.
“Once the amyloid beta assemblies grow, the signal becomes weaker and broader until it disappears because the technique can only analyze small molecules,” said Peng. “But when we add in midkine, the signal returns, showing that it inhibits the large assemblies.”
Additionally, the researchers used Alzheimer’s disease mouse models that have increased amyloid beta and demonstrated that removing the midkine gene resulted in even higher levels of amyloid beta assemblies. These results point to the protective role the protein has against Alzheimer’s disease.
The researchers have opened a potential avenue for drug discovery by identifying the apparent protective role of midkine. “We want to continue to understand how this protein binds to amyloid beta so we can design small molecules to do the same thing,” said Peng. “With this work, we hope to provide strategies for future treatment.”
Authors and funding
The study’s other co-corresponding authors are Yang Yang, Van Andel Institute, and Ping-Chung Chen, St. Jude. The study’s first authors are Masihuz Zaman, Shu Yang and Ya Huang, St. Jude. The study’s other authors are Geidy Serrano and Thomas Beach, Banner Sun Health Research Institute; Gang Yu, University of Texas Southwestern Medical Center; and Jay Yarbro, Yanhong Hao, Zhen Wang, Danting Liu, Kiara Harper, Hadeer Soliman, Alex Helphill, Sarah Harvey, Shondra Pruett-Miller, Valerie Stewart, Ajay Singh Tanwar, Ravi Kalathur, Christy Grace, Martin Turk, Sagar Chittori, Yun Jiao, Zhiping Wu, Anthony High, and Xusheng Wang, St. Jude.
The study was supported by the National Institutes of Health (R01AG053987, RF1AG064909, RF1AG068581, U19AG069701, P30CA021765, U24NS072026, P30AG019610, P30AG072980), the Arizona Department of Health Services, the Arizona Biomedical Research Commission, the Michael J. Fox Foundation for Parkinson’s Research and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.