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Human umbilical blood rejuvenates old mice brains
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 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.
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."
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.
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.
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.
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.
The hippocampus (colored GREEN) is critical to spatial learning and memory.
Image Credit: adapted from the UCSF Memory and Aging Center videos