20 Apr 2017

Umbilical cord blood, prized as a source of rejuvenating stem cells, now can lay another claim to fame. In the April 19 Nature, researchers led by Tony Wyss-Coray at Stanford University report that proteins from human cord blood improve learning and memory when injected into aged mice. Just a few proteins from the cord plasma, most notably a metalloproteinase inhibitor called TIMP2, were sufficient. Injecting TIMP2 alone into aged mice revitalized their hippocampi, improving neural plasticity and performance on several memory tests.

The researchers have yet to figure out how this one protein has such profound effects, but already they think the findings will help scientists get a better grip on age- and disease-related cognitive decline in people, and might even reveal ways to slow or prevent it. “TIMP2 came as a complete surprise,” said Wyss-Coray. “While it may be a challenge to figure out how this protein works at the molecular level, the trade-off may be its broad activity,” he told Alzforum.

Wyss-Coray’s lab has pioneered the uses of parabiosis in aging research. The procedure melds the vasculature of two animals together, enabling investigations of how young blood might energize older animals. His group found that young mouse blood harbors a variety of factors that protect older mice against aging (see May 2014 conference news; Jul 2015 news). Now, first author Joseph Castellano and colleagues have broached the question of, “Does this work in humans?” They asked if rejuvenating factors can be identified in young human plasma, such as from umbilical cords.

Brain Penetrant. Radiolabeled TIMP2 injected into the peritoneum makes its way into the mouse brain. [Image courtesy Tony Wyss-Coray and Nature.]

Castellano began by measuring levels of 66 common plasma proteins in samples from stored umbilical cords, young adults aged 19 to 24, and older people aged 61to 82. He noted that there were distinct panels of proteins in each age group. To test if this difference was functionally important, he infused plasma from each age group into the veins of 14-month-old mice every four days and two weeks later looked for changes in gene expression in the brain. The researchers used immunodeficient mice to avoid immune responses against the human proteins. These mice age just like wild-type; their neurogenesis and activation of immediate-early genes wanes while microgliosis rises as they mature.

Castellano found that the older human plasma proteins had little effect on those established markers of age. However, using whole-genome microarray analysis, he discovered that the plasma from young adults and from umbilical cords boosted expression of genes involved in neural plasticity. Moreover, the cord plasma activated clusters of genes known to be involved in memory, including c-fos and other intermediate-early genes. In quantitative analysis of specific gene expression patterns, Castellano found that the young adult blood proteins activated some, but not all, of those genes activated by cord blood.

Did these gene activations affect how the brain functions? Electrophysiology of hippocampal slices from the infused mice revealed stronger long-term potentiation (LTP), a sign of improved neural plasticity, only in mice that had received cord plasma. Cord-plasma-infused animals escaped the Barnes maze sooner than untreated mice, and they learned the task faster, both indications of better spatial memory. They froze more readily in a fear-conditioning test, a response that relies on hippocampal memory. Plasma proteins from young and older adults did not achieve these effects.

Next, Castellano performed a customized protein microarray analysis to look for age-related changes human and mouse plasma have in common. He thought he might identify factors responsible for the youthening effect of the cord blood. This unbiased approach yielded very similar profiles from human and mouse blood. Next, Castellano chose likely candidates that happened to be available as recombinant proteins and injected them into the peritonea of wild-type (C57Bl/6) mice. Low and behold, TIMP2 and colony stimulating factor 2 (CSF2) activated the immediate early gene c-fos in the brain. The effect of TIMP2 was unexpected, so the researchers dug further.

They went on to discover that TIMP2 expression in the brain declines with age, particularly in the subgranular and hilar areas of the dentate gyrus. Recombinant TIMP2 readily crosses the blood-brain barrier (see image above), and over a two-week regimen of four doses every other day, it improved LTP and learning and memory in aged mice. The animals even started building nests, something older mice lose interest in.

What’s more, antibodies against TIMP2 suppressed LTP in hippocampal slices from wild-type mice, and worsened their performance in an object-recognition task. Immunodepleting cord plasma of TIMP2 also neutralized its effects on LTP and memory in wild-type mice.

What might TIMP2 do in the brain? Wyss-Coray said that’s an open question, but noted that because it regulates matrix metalloproteinases, a family of 20 or more enzymes, it likely has many functions. Castellano found that many immune and trophic factors were upregulated in the blood of TIMP2 knockout mice, suggesting it may have a profound effect on the systemic and even the brain’s “communicome.” Wyss-Coray wondered if TIMP2 suppresses signals from senescent cells, including microglia and astrocytes, which help drive the aging process.—Tom Fagan

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References

News Citations

1. In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition 5 May 2014
2. β2-Microglobulin: A Blood-Borne Aging Factor? 10 Jul 2015

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