In a recent study published in the journal Science Advances, a team of Chinese researchers used murine models to investigate whether immune rejuvenation through the transplantation of young bone marrow could retard immunosenescence and potentially be used as a therapeutic strategy for Alzheimer's disease.
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Background
An increasing number of studies are reporting the involvement of immune system dysfunction in the pathogenesis of Alzheimer's disease. Additionally, it has been observed that close to 50% of the genes involved in Alzheimer's disease, such as BIN1, which codes for bridging integrator 1, CD33, which codes for a myeloid cell surface antigen, and triggering receptor expressed on myeloid cells 2 (TREM2), are genes that are involved in immune system processes.
The age-related decline of the immune system results in a decrease in immune cell production, reduced diversity of the immune repertoire, and an accumulation of dysfunctional immune cells — a phenomenon collectively known as immunosenescence. It is believed that immunosenescence is a driver of systemic aging, including brain aging, and increases the susceptibility to age-related degenerative diseases such as Alzheimer's disease. Therefore, it can be assumed that the rejuvenation of immune cells would positively impact slowing the progression of Alzheimer's disease.
About the study
In the present study, the researchers used nine-month-old transgenic Alzheimer's disease model mice and transplanted them with the bone marrow from younger (two-month-old) Alzheimer's disease model mice. In the control group, the mice were transplanted with bone marrow from similar nine-month-old mice.
The researchers hypothesized that the hematopoietic stem cells, which give rise to peripheral immune cells, in the bone marrow of younger mice could rejuvenate the aging immune cells and provide a potential therapeutic strategy against Alzheimer's disease. Peripheral blood mononuclear cells (PBMCs) were characterized to determine alterations in the gene expression of peripheral immune cells.
Studies have reported that peripheral lymphohematopoietic cells reconstitute approximately three weeks after the bone marrow transplant. Therefore, the researchers hypothesized that the effects of anti-Alzheimer's disease would be displayed after three weeks, and they conducted behavior tests such as the Y-maze and open-field tests to assess brain function.
The PBMCs were analyzed to assess the impact of old and young bone marrow on the immune cell composition of recipient mice. The proportion of B cells, helper T cells, cytotoxic T cells, monocytes, macrophages, dendritic cells, neutrophils, basophils, and natural killer cells were determined.
Additionally, tests such as the amyloid β phagocytosis and cell debris phagocytosis assays were conducted to assess monocyte function. Brain sections from euthanized mice were then stained for immunohistochemistry analysis and immunofluorescence tests. The brain sections were stained to determine amyloid β plaques and neurodegeneration based on neuronal apoptosis and loss and degeneration of neurites.
The brain sections were also used to analyze brain volume and conduct western blotting to detect amyloid β and full-length amyloid precursor protein. Inflammatory factors such as interleukin-10, interferon-γ, and tumor necrosis factor-α were assessed using enzyme-linked immunosorbent assay.
Total ribonucleic acid (RNA) extracted from the monocytes was used for quantitative reverse transcription polymerase chain reaction (qRT-PCR), while the microglia were used for bulk-RNA sequencing. In addition, the plasma proteome was evaluated using liquid chromatography-tandem mass spectrometry.
The single-cell RNA sequencing data was analyzed to identify cell types and for differential gene expression, transcription factor regulatory network analysis, cell-to-cell communication assessment, and pathway enrichment.
Results
The study found that young bone marrow transplantation significantly reduced neuronal degeneration, amyloid β plaque burden, and neuroinflammation and improved the behavioral deficits observed in aged Alzheimer's disease model mice. Increased amyloid β clearance was also found to ameliorate cerebral amyloidosis.
The single-cell RNA data indicated that the expression of various Alzheimer's disease and aging-related genes was restored in various immune cell types after young bone marrow transplantation. Furthermore, the circulatory levels of secretory proteins associated with senescence were lower after the bone marrow transplantation.
The researchers found that among the aging-related differentially expressed genes, the Alzheimer's disease risk genes showed the highest expression in monocytes. Since circulatory monocytes can clear amyloid β, the age-related impairment of amyloid β phagocytosis by monocytes can accelerate plaque formation. Therefore, the rejuvenation of monocytes along with other immune cells through young bone marrow transplantation presents a promising therapeutic strategy.
Conclusions
To summarize, the findings supported the effectiveness of young bone marrow transplantation in rejuvenating aging immune cells, which reduced neuronal degeneration in a murine Alzheimer's disease model. The improved monocyte function resulted in increased clearance of amyloid β and decreased neuronal inflammation.
The behavioral deficits observed in the aging Alzheimer's disease mice model were also found to improve after the transplantation of bone marrow from younger mice. Cumulatively, these results suggested that young bone marrow transplantation is a promising treatment strategy for Alzheimer's disease.
Journal reference:
- Sun, P., Liu, J., Hu, J., Tu, Y., Jiang, Q., Jia, Y., Sun, H., Chen, S., Xin, J., Yu, Z., Liu, Z., Tan, C., Zeng, G., Shi, A., Liu, Y., Bu, X., Wang, Y., & Wang, J. (n.d.). Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model. Science Advances, 10(22), eadl1123. DOI: 10.1126/sciadv.adl1123, https://www.science.org/doi/full/10.1126/sciadv.adl1123
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