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.
Highlights
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
Circulating levels of the C–C motif chemokine ligand 11 (CCL11, known as eotaxin-1) and β2-microglobulin have previously been reported to increase with age in mice and humans, and shown to promote brain aging when administered to young mice[3,10,11]
CCL11 and β2-microglobulin are thought to act by suppressing neurogenesis in the hippocampus, because neurogenesis was enhanced in old mice rejuvenated by parabiosis or plasma transfer, and injection of CCL11 or β2-microglobulin into young mice suppressed neurogenesis[3,10]
Summary
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. Circulating levels of the C–C motif chemokine ligand 11 (CCL11, known as eotaxin-1) and β2-microglobulin have previously been reported to increase with age in mice and humans, and shown to promote brain aging when administered to young mice[3,10,11] Both CCL11 and β2-microglobulin can be produced by a diverse range of cell types, and the tissue(s)/organ (s) responsible for their elevated levels during aging have not been defined. We established a heterochronic bone marrow transplant (BMT) model to determine the specific influence of systemic hematopoietic aging on cognitive function, including glial cells in the hippocampus This approach allowed us to evaluate the long-term beneficial impact of a young hematopoietic system on the aging brain, and define the role of the hematopoietic system in aging-associated elevation of circulating levels of CCL11 and β2-microglobulin. Irradiation (9 Gy, split dose) delivered without head shielding prior to injection of donor bone marrow cells enabled us to exclude the impact of neurogenesis, because irradiation is known to inhibit the proliferation of neural progenitors[15,16]
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