Discipline: Neuroscience
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)
Session: 1
Room: Council
Aarun Hendrickson - University of Washington
Co-Author(s): Shannon Hu, University of Washington, Washington, Seattle; Kathy Cui, University of Washington, Washington, Seattle; Kendra Francis, University of Washington and Seattle Children's Research Institute, Washington, Seattle; Bao Anh Phan, University of Washington, Washington, Seattle; Tammy Doan, University of Washington, Washington, Seattle; Rhea Nanavati, University of Washington, Washington, Seattle; Gail Deutsch, Seattle Children's Research Institute, Washington, Seattle; Sai Shilpa Kommaraju, Barrow Neurological Institute, Arizona, Pheonix; Elaine Cabrales, Barrow Neurological Institute, Arizona, Phoenix; Zaman Mirzadeh, Barrow Neurological Institute, Arizona, Phoenix; Aimee Schantz, University of Washington, Washington, Seattle; Amber Nolan, University of Washington, Washington, Seattle; Caitlin Latimer, University of Washington, Washington, Seattle; C. Dirk Keene, University of Washington, Washington, Seattle; Michael W. Schwartz, University of Washington, Washington, Seattle; Jarrad M. Scarlett, University of Washington and Seattle Children's Research Institute, Washington, Seattle; andKimberly M. Alonge, University of Washington, Washington, Seattle.
Aging is associated with shifts in the composition of brain extracellular matrix chondroitin sulfate glycosaminoglycans (CS-GAGs). CS-GAGs are comprised of repeating glucosamine and N-acetylgalactosamine units that are either non-sulfated (0S-CS), mono-sulfated (4S-CS, 6S-CS), or di-sulfated (2S6S-CS, 4S6S-CS, 2S4S-CS/Dermatan) and participate in the regulation of brain plasticity. The mono-sulfated 6S-CS isomer is predicted to play a key role in the induction of circuit plasticity during neurodevelopment, therefore we asked whether this isomer also shows age-related changes in both wild-type mice and in humans. Our preliminary data generated from cohorts of mice ranging in age from 10 days to 2 years (50%M / 50% F) reveal that 6S-CS abundance is highest at 10 days of age (38.8±0.9%) and then steadily declines with increasing age: 14 days (30.2±0.5%), 21 days (23.7±0.3%), 42 days (16.2±0.2%), 3 months (6.7±0.1%), 6 months (5.7±0.1%), 12 months (5.1±0.1%), 18 months (4.8±0.1%), and 24 months (5.1±0.2%) of age (mean±SE; 5-27 mice/group). We then analyzed the relative abundance of the 6S-CS isomer in n=54 hippocampal human brain tissue samples (age: newborn – 95 years, sex: 50%M / 50% F). Initially, the human hippocampus exhibited the highest abundance of 6S-CS isomer following birth (<1 month age; (19.8±3.5%)) that then declined at >1M to 9 years (10.2±1.9%), 10-19 years (11.0±1.3%), and 20-29 years (5.5±0.7%) years of age phenocopying the results from mice. However, in contrast to mice in which 6S-CS abundance decreased progressively with aging, we found that in humans that hippocampal 6S-CS abundance began to increase again starting at 30-39 years (8.3±0.5%), 40-49 years (7.9±0.5%), 50-59 years (7.9±0.9%), 70-79 years (9.7±0.7%), 80-89 years (8.9±0.6%), and 90-99 years (11.4±2.4%) of age (R2 = 0.44, p-0.0001). Collectively, these findings demonstrate that age-associated changes in brain extracellular matrix 6S-CS isomer abundance in human hippocampus do not reflect the age-related decline of 6S-CS isomers that occur in mouse hippocampus. Therefore, additional research is needed to establish the utility and robustness of using rodent models to study aging and other age-related extracellular matrix diseases in humans.
Funder Acknowledgement(s): DK122662 (KMA), DK101997 (MWS), DK720269 (MWS), DK114474 (JMS), DK017047 (KMA, JMS), AG066509 (UW ADRC), AG006781 (ACT), RRF A139339 (JMS), BR013035 (KMA), (A161703 JMS).
Faculty Advisor: Kimberly Alonge, kalonge@uw.edu
Role: I conducted work on each step of the project to some extent. Primarily, I did tissue collection of the mice brains, processed both human and mouse tissue, and prepped samples for mass spectrometry analysis. For the mouse tissue collection, I worked alongside others to both perfuse and extract the brain. Following, I lead the washing of the tissue and adding the appropriate enzymes to isolate the CS-GAG isomers in the collected samples. After the isomers were left in their solutions, I went through a series of steps to assure the liquid was ready to be analyzed on the mass spectrometer.