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Human umbilical blood rejuvenates old mice brains

Human umbilical cord blood can rejuvenate learning and memory in older mice, according to a study at the Stanford University School of Medicine. TIMP2 is a protein abundant in cord blood, but decreases with advancing age. Cord blood injected into older mice improved their memory performace.

In a widely discussed earlier study, senior author Tony Wyss-Coray PhD, professor of neurology and neurological sciences and a senior research scientist at the Veterans Affairs Palo Alto Health Care System, showed that direct infusion of young mouse plasma — the colorless fluid part of blood without any cells — benefited old mice. His team found those benefits improved performance on mouse memory tests and learning.

This new study is the first to demonstrate that human plasma can assist memory and learning in an older mouse. Both Wyss-Coray and lead author Joseph Castellano PhD, instructor of neurology and neurological sciences, believe it will have a similar affect on people. They also suggest it's promising from a drug-development standpoint, as a single protein appears largely capable of mimicking those benefits.

Investigators compared human blood plasma from:
(1) umbilical cord blood
(2) 19 to 24 year-olds
(3) 61 to 82 year-olds
Finding proteins in each which appear age related.

Investigators suspected these changes, might affect the hippocampal brain. In both mice and humans the hippocampus is critical for converting experience into long-term memory. In particular, it is essential to spatial memory, i.e. how to find your car parked in a multilevel structure hours before, or autobiographical events, such as what you ate for breakfast.

"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."

Tony Wyss-Coray PhD, Professor, Neurology and Neurological Sciences, Senior Research Scientist, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.

The study was published online April 19 in Nature. Researchers hope their findings lead to new treatments for age-associated declines in mental ability.

For largely unknown reasons, the hippocampus is especially vulnerable to normal aging, adds Wyss-Coray. "With advancing age, the hippocampus degenerates, loses nerve cells and shrinks." 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, researchers tested immune-deficient laboratory mice that could be given repeated injections of human plasma without experiencing negative immune reactions. Previous experiments injecting human plasma into 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, uses a of 4 foot, round table that is 1.3 feet high, brightly lit and open on all sides — factors that make mice feel insecure. It is also full of holes, only one of which attaches to a tube where a scared mouse can find darkness and safety. The other holes drop to the floor from a height not physically harmful to a mouse, but scary. The hole with a burrowing tube can be changed from one session to the next. Visual cues to its location can also be changed to guide the mouse to the protected "escape."

Older mice that received human umbilical-cord blood plasma every fourth day for two weeks, had many measures of hippocampal function notably improve.

Plasma from older people, on the other hand, didn't help at all, while young-adult plasma induced an intermediate effect.

Older mice's performance on the Barnes maze and other tests was stellar compared with mice of the same age injected with 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 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 that activity a great deal.

Tissue inhibitor of metalloproteases 2— or TIMP2, belongs to a well-known family of four TIMPs that regulate proteins by chopping up yet more proteins in the cell matrix where they are embedded.

TIMP proteins are natural inhibitors of matrix metalloproteinases (MMPs), known as matrixins, that break peptide bonds inside molecules. Part of a large family of enzymes, matrixins degrade extracellular matrix proteins — proteins secreted to provide structure and biochemical support to a cell. They are distinguished from other endopeptidases by their dependence on metal ions — such as the heme or iron-containing oxygen-transport in the red blood cells of all vertebrates. TIMP2 appears to stop matrixins in their breakdown of cellular structure in the hippocampus.

Injecting TIMP2 by itself into elderly mice largely duplicated the beneficial effects of umbilical-cord plasma. It even restored mouse nesting as these mice began using cotton wads, supplied by researchers, to build nests for sleep — an instinctive behavior largely lost in old age. But older mice that were given human cord plasma depleted of TIMP2 derived no learning and memory benefits. While injecting TIMP2 neutralizing antibodies in young, normal mice — who ordinarily perform well on memory tests — obliterated their skills.

"TIMP2's effects in the brain have been studied a little, but not much — and not in aging. 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."

Joseph M. Castellano PhD, Instructor, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA and lead author.

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 potentiation1, 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 potentiation2, 3, 4 and downregulated in the aged brain5, 6, 7, 8. In addition to revitalizing other aged tissues9, 10, 11, 12, 13, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters14, 15, 16, 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.

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.

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.

The 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.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med.stanford.edu.
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The hippocampus (colored GREEN) is critical to spatial learning and memory.
Image Credit:
adapted from the UCSF Memory and Aging Center videos


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