Cognitive decline is an expected part of normal ageing; however, it can be exacerbated as a result of neurological damage or disease. Many studies have shown improved cognitive function to be attributed to increased neurogenesis (production of neuronal cells) and synaptic plasticity (the change in strength of synapses in the brain), as well as better brain vascularisation (blood supply) and myelination (covering of neurones by a protective and insulating tissue called myelin sheath). Parabiosis has also recently been shown to have similar effects.
Parabiosis is the union (natural or surgical) of anatomical parts of 2 organisms, usually involving exchange of blood. Heterochronic parabiosis is parabiosis between 2 organisms of different ages. Recent studies surgically attaching old mice to young mice so that they share a circulatory system have been reported to rejuvenate old mice and accelerate ageing in young mice. A single blood exchange between the mice, which replaces the blood without organ sharing or complications of the parabiosis procedure, has also recently been reported to have similar effects.
CCL11 and β2-microglobulin are proteins that have been reported to increase with age in mice and humans, shown to suppress neurogenesis and promote brain ageing when given to young mice. Cognitive function restoration in old mice by transfer of blood or plasma from young mice has been attributed to reduced CCL11 and β2-microglobulin. However, the specific role of the haematopoietic (blood) system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear.
In this study, the researchers established a heterochronic bone marrow transplant (BMT) model to determine the specific influence of systemic haematopoietic ageing on cognitive function. This approach allowed them to evaluate the long-term beneficial impact of a young haematopoietic system on the ageing brain and define the role of the haematopoietic system in ageing-associated elevation of circulating levels of CCL11 and β2-microglobulin. The impact of neurogenesis was excluded through radiation exposure before bone marrow cell injection because radiation inhibits growth of neurones, and so the results shown will have been solely due to the impact of the haematopoietic system.
2 different ages were used to represent young and old mice; 18-month for old and 4-month for young. Reconstituted mice received 2 million young or old donor bone marrow cells. The table below shows the types/groups of mice used.
|Mice age||Control||Reconstituted (young or old bone marrow transferred)|
|4-month old mice||Young mice|
|18-month old mice||Old mice||Old mice + young BMT
Old mice + old BMT
Exploratory behaviour and hippocampus-dependent learning and memory were evaluated using a Y-shaped maze, and the spontaneous alternation of the mice between the 3 arms of the maze was recorded for 8 mins. In the maze, old control mice performed worse than young control mice, but young bone marrow recipients completed more spontaneous alternations between the arms of the maze than both old bone marrow recipients and old control mice. This suggests that young BMT preserves spatial and working memory in old mice.The mice underwent several tests, each exploring a specific aspect of their cognition, learning, and memory amongst other characteristics.
Learning, spatial memory and memory recall were assessed using a Barnes maze, in which mice were trained to find an escape box and later tested on the number of errors made and time taken to find the escape box after training, and again repeated after the escape box was moved to the opposite side of the maze. Compared to old control mice and old bone marrow recipients, young control mice and young bone marrow recipients made fewer errors when locating an escape hole during the training phase, during the actual testing phase and after the escape hole had been moved. However, the time taken to successfully complete the test was similar across all groups. Together, these results show that a young haematopoietic system maintains recall ability in old mice.
The researchers also investigated whether heterochronic BMT impacts the levels of circulating factors previously implicated in brain ageing, focusing on β2-microglobulin and CCL11. They observed higher plasma levels of both proteins in old control mice than young control mice. Notably, however, plasma levels of CCL11, but not β2-microglobulin, were reduced in recipients of young (but not old) bone marrow. This suggests that non-haematopoietic cells are the main source of β2-microglobulin in old mice, while CCL11 is either derived from haematopoietic cells or produced by non-haematopoietic cells under the influence of haematopoietic cells. Additionally, it raises the possibility that reduced CCL11 production may underlie the preservation of cognitive function in old mice following young BMT.
The results of this study found that reconstitution of old mice with young, but not old, hematopoietic cells reduce cognitive decline. BMT preserved cognitive function for at least 6 months, despite suppression of neurogenesis. The data also attribute the ageing-associated elevation of circulating β2-microglobulin levels to non-hematopoietic cells. In contrast, the increased CCL11 appears either to be of hematopoietic origin or to be produced by non-hematopoietic cells under hematopoietic control.
The results of this study further demonstrate that restoration of neurogenesis is not essential for the preservation of cognitive function, and that young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative and ageing-associated diseases such as Alzheimer’s and Parkinson’s disease.
Original Source: Das, M.M., Godoy, M., Chen, S. et al. (2019). “Young bone marrow transplantation preserves learning and memory in old mice.” Communications Biology 2, 73. https://doi.org/10.1038/s42003-019-0298-5
Link to Study: https://doi.org/10.1038/s42003-019-0298-5
Edited by Cyrus Rohani-Shukla