UCSF study finds that an exercise-induced liver protein strengthens the blood-brain barrier, improving memory and slowing age-related decline.
Researchers at UC San Francisco have discovered a mechanism that could explain how exercise improves cognition by shoring up the brain's protective barrier.
With age, the network of blood vessels — called the blood-brain barrier — gets leaky, lettingharmful compounds enter the brain. This causes inflammation, which is associated with cognitive decline and is seen in conditions like Alzheimer's disease.
Six years ago, the team identified a brain-rejuvenating enzyme called GPLD1 that mice produced in their livers when they exercised. But they couldn't understand how it worked, because it cannot get into the brain.
The new study answers that question. Researchers discovered that GPLD1 was working through another protein called TNAP. As the mice age, the cells that form the blood-brain barrier accumulate TNAP, which makes it leaky. But when mice exercise, their livers produce GPLD1. It travels to the vessels that surround the brain and trims TNAP off the cells.
"This discovery shows just how relevant the body is for understanding how the brain declines with age," said Saul Villeda, PhD , associate director of the UCSF Bakar Aging Research Institute .
Villeda is the senior author of the paper, which was published in Cell on Feb. 18 .
To begin to understand how GPLD1 works on the brain, the team considered its main job: cutting certain proteins from the surface of cells. Then, they searched for tissues that had proteins on their surface that could be cut by the enzyme. They guessed that some tissues probably accumulatedmore of these proteins with age.
The cells that make up the blood-brain barrier stood out. They had several GPLD1 targets dotting their surface, but when the researchers exposed of the each targets to GPLD1 in test tubes, it only cut one of them: TNAP.
Young mice engineered to have more TNAP in the blood-brain barrier lost their cognitive abilities as if they were old.
When the researchers used genetic engineering tools to reduce the amount of TNAP in 2-year-old mice — which are the equivalent of 70 human years — their blood-brain barrier became less leaky,and their brain inflammation went down. The mice also performed better on memory tests.
"We were able to tap into this mechanism late in life, for the mice, and it still worked," said Gregor Bieri, PhD, a postdoctoral scholar in Villeda's lab and co-first author of the study.
Finding drugs to trim proteins like TNAP could be a new way to rejuvenate the blood brain barrier,even after it's been degraded by age.
"We're uncovering biology that Alzheimer's research has largely overlooked," Villeda said. "It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain."
Authors: Other UCSF authors are Karishma Pratt, PhD; Yasuhiro Fuseya, MD, PhD; Turan Aghayev, MD; Juliana Sucharov; Alana Horowitz, PhD; Amber Philp, PhD; Karla Fonseca-Valencia, degree; Rebecca Chu; Mason Phan; Laura Remesal, PhD; Andrew Yang, PhD; and Kaitlin Casaletto, PhD. For all authors, see the paper.
Funding: The study was supported in part by National Institutes of Health (AG081038, AG086042, AG082414, AG077770, AG067740, P30 DK063720); Simons Foundation; Bakar Family Foundation; Cure Alzheimer's Fund; Hillblom Foundation; Glenn Foundation; JSPS; Japanese Biochemistry Postdoctoral Fellowship; Multiple Sclerosis Foundation; Frontiers in Medical Research; American Federation for Aging Research; National Science Foundation; Bakar Aging Research Institute; Marc and Lynne Benioff.
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health , which serves as UCSF's primary academic medical center, includes among the nation's top specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at ucsf.edu or see our Fact Sheet .
