Umbilical cord blood from human newborns, and in particular a single protein contained in it, boosted old mice’s brain function and cognitive performance, new research from Stanford shows.
Human umbilical cord blood can rejuvenate learning and memory in older mice, according to a study by researchers at the Stanford University School of Medicine.
The researchers identified a protein, abundant in human cord blood but decreasingly so with advancing age, that had the same effect when injected into the animals.
The findings could lead to new treatments for age-associated declines in mental ability.
“Neuroscientists have ignored it and are still ignoring it, but to me it’s remarkable that something in your blood can influence the way you think,” said the study’s senior author, Tony Wyss-Coray, PhD, professor of neurology and neurological sciences and a senior research career scientist at the Veterans Affairs Palo Alto Health Care System. The lead author is former postdoctoral scholar Joseph Castellano, PhD, who is now an instructor of neurology and neurological sciences.
The study was published online April 19 in Nature.
In a widely discussed earlier study, Wyss-Coray’s lab showed that direct infusion of young mice’s plasma, the cell-free portion of blood, benefited old mice. Those benefits extended beyond biochemistry and physiology to actual performance on tests of memory and learning, the researchers found.
The new study marks the first demonstration that human plasma can aid older mice’s memory and learning, which both Wyss-Coray and Castellano said would seem to increase the likelihood that it could have a similar beneficial effect in people. It’s also promising from a drug-development standpoint, they suggested, that a single protein appears largely capable of mimicking those benefits.
Age-associated changes in blood
Comparing blood plasma from 19- to 24-year-olds, 61- to 82-year-olds and umbilical cords, researchers identified age-associated changes in a number of proteins.
These changes, the investigators suspected, might affect a brain structure called the hippocampus, which in both mice and humans is critical for converting experiences into long-term memories. In particular, the hippocampus is essential for helping you remember spatial information, such as how to find your way back to the car you parked in a multilevel structure several hours ago, and information about autobiographical events, such as what you ate for breakfast.
For largely unknown reasons, the hippocampus is especially vulnerable to normal aging, said Wyss-Coray. “With advancing age, the hippocampus degenerates, loses nerve cells and shrinks,” he said. The capacity to learn and remember falters in lockstep. Hippocampal deterioration is also an early manifestation of Alzheimer’s disease.
To distinguish the effects of old, young and “youngest” human blood on hippocampal function, the researchers used immune-deficient laboratory mice that could be given repeated injections of human plasma without experiencing negative immune reactions. Experiments undertaken before injecting human plasma into the mice showed that, like their immune-competent peers, these mice’s hippocampal activity, integrity and regenerative capacity dropped off in old age — indeed, a bit faster.
Old immune-deficient mice performed more poorly than younger ones on tests of memory and learning. One such test, the Barnes maze, employs a table, about 4 feet in diameter and 1.3 feet high, that is brightly lit and open to the surrounding environment — two factors that make mice feel insecure. The table is also full of holes, one of which is attached to a tube in which a scared mouse can find darkness and safety. The other holes offer only a drop to the floor from a height that would not physically harm a mouse but is enough deter one. Which hole has a burrowing tube attached to it can be changed from one session to the next. Visual cues to its location can also be transferred to help guide the mouse to the escape hole, memory permitting.
Improvements in hippocampal function
When the older mice received human umbilical-cord blood plasma every fourth day for two weeks, many measures of hippocampal function improved notably. Plasma from older people, on the other hand, didn’t help at all, while young-adult plasma induced an intermediate effect. And older mice’s performance on the Barnes maze and other tests was stellar in comparison with mice of the same age who got injections of saline instead of plasma.
Something in umbilical cord blood was making old brains act younger. To find out what it was, Wyss-Coray and his colleagues gauged plasma-protein levels in humans and mice from different age groups, in search of proteins that the two species share in common and whose levels change similarly with age. One protein in particular grabbed their attention: In a laboratory test designed to discern a substance’s ability to enhance nerve-cell activity in the brain, it triggered this activity to a great degree. The protein, called tissue inhibitor of metalloproteases 2, or TIMP2, belongs to a well-known family of four TIMPs that regulate the activity of other proteins whose function is to chop up yet other proteins occupying the matrix in which cells are embedded.
Injecting TIMP2 by itself into elderly mice largely duplicated the beneficial effects of umbilical-cord plasma. It even restored these mice’s nesting capacity: an instinctive penchant, largely lost in old age, for using available materials, such as cotton wads supplied by the researchers, to build nests in which mice typically prefer to sleep. But old mice that were given human cord plasma depleted of TIMP2 derived no learning and memory benefits. And administering TIMP2-neutralizing antibodies to young normal mice, who ordinarily perform well on memory tests, obliterated their prowess.
“TIMP2’s effects in the brain have been studied a little, but not much and not in aging,” said Castellano. “In our study, it mimicked the memory and learning effects we were getting with cord plasma. And it appeared to do that by improving hippocampal function.”
Stanford’s Office of Technology Licensing has filed for patents related to the findings in the study. Alkahest, a biotechnology company based in San Carlos, California, in which Castellano and Wyss-Coray hold equity and which Wyss-Coray co-founded, has licensed rights to this intellectual property.
Other Stanford co-authors of the study are former graduate student Kira Mosher, PhD; former research assistant Rachelle Abbey; research technician Alisha McBride; research scientist Daniela Berdnik, PhD; research associate Jadon Shen; research nurse manager Martha Tingle, RN; former mass-spectroscopy specialist Izumi Hinkson, PhD; Xinmin Xie, MD, PhD, a consulting associate professor of anesthesiology, perioperative and pain medicine; Michelle James, PhD, assistant professor of radiology and of neurology and neurological sciences; and Martin Angst, MD, professor of anesthesiology, perioperative and pain medicine.
Funding: TThe study was funded by the National Institute on Aging (grants K99AG051711, AG045034, DP1AG053015 and AG040877), the Jane Coffin Childs Foundation, the Simons Foundation, the U.S. Department of Veterans Affairs, the Glenn Foundation for Medical Research and the Stanford Brain Rejuvenation Project.
Stanford’s Department of Neurology and Neurological Sciences also supported the work.
Source: Bruce Goldman – Stanford
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Human umbilical cord plasma proteins revitalize hippocampal function in aged mice” by Joseph M. Castellano, Kira I. Mosher, Rachelle J. Abbey, Alisha A. McBride, Michelle L. James, Daniela Berdnik, Jadon C. Shen, Bende Zou, Xinmin S. Xie, Martha Tingle, Izumi V. Hinkson, Martin S. Angst & Tony Wyss-Coray in Nature. Published online April 19 2017 doi:10.1038/nature22067
Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain.
In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown17. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice.
Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma.
We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.
“Human umbilical cord plasma proteins revitalize hippocampal function in aged mice” by Joseph M. Castellano, Kira I. Mosher, Rachelle J. Abbey, Alisha A. McBride, Michelle L. James, Daniela Berdnik, Jadon C. Shen, Bende Zou, Xinmin S. Xie, Martha Tingle, Izumi V. Hinkson, Martin S. Angst & Tony Wyss-Coray in Nature. Published online April 19 2017 doi:10.1038/nature22067