Synapses in the brain are preserved by transplanting young bone marrow into older individuals, according to an open-access mouse study published in Communications Biology.
Blood and marrow
Simply exchanging blood itself has been shown to have only limited positive effects on cognition. Irina and Michael Conboy have been performing plasma transfer experiments and experiments in which cells are cultivated in a mix of old and young serum; in our recent interview with them, the Conboys were clear that “the old serum wins.” For the hippocampus, old blood is a much greater inhibitor of growth than young blood is a promoter, and the Conboys and other researchers confirmed this in an experiment [1]. Apheresis, the removal of negative factors from blood, may be an effective solution, but attempting to restore youthful cognition through blood transfusions does not appear to be a feasible human therapy.
However, what if we replaced marrow rather than just blood? Bone marrow is, after all, the source of red blood cells; this process is called hematopoiesis. If young marrow were transplanted into old animals, rejuvenating the source of blood rather than just temporarily and partially affecting the blood itself, it might have long-lasting positive effects, and this is what this research team attempted to find out.
The experiment
The mice were irradiated prior to transplantation; this is typical for bone marrow transplants, as it destroys the existing marrow and prevents immunorejection. As this irradiation was conducted without head shielding, it strongly inhibited neurogenesis (the formation of new neurons).
However, it was very effective in encouraging existing neurons to form new synapses, a process that is inhibited in older animals. CCL11 is a blood factor that causes negative downstream effects, encouraging microglia to reduce synapse growth, and the young marrow reduced this factor. The resulting increase in learning ability was shown in cognitive tests; mice given young marrow performed better in most aspects of standard maze tests, including spatial and working memory, than both old control mice and mice given old marrow.
Further experiments may be conducted with head shielding in order to examine the effects of marrow transplantation on neurogenesis.
Abstract
Restoration of cognitive function in old mice by transfer of blood or plasma from young mice has been attributed to reduced C–C motif chemokine ligand 11 (CCL11) and β2-microglobulin, which are thought to suppress neurogenesis in the aging brain. However, the specific role of the hematopoietic system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear. Here we report that transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis, and without reducing β2-microglobulin. Instead, young bone marrow transplantation preserved synaptic connections and reduced microglial activation in the hippocampus. Circulating CCL11 levels were lower in young bone marrow recipients, and CCL11 administration in young mice had the opposite effect, reducing synapses and increasing microglial activation. In conclusion, young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative disease.
Conclusion
As usual, the standard caveat of murine research applies: mice are not people, and human marrow recipients may have their neurons, and other cells, affected in ways that cannot be discovered in a purely murine study.
This study does offer hope for people suffering from age-related brain deterioration, however, and as marrow transplants are already being performed in humans, one next logical step would be to test cognition in people who have received them. As CCL11 is known to affect both mice and people, downregulating this protein through apheresis, marrow transplants, or some other method would also be worth studying.
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Literature
[1] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7, 13363.
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