Young bone marrow transplants may reverse symptoms of Alzheimer's disease

In a recent study published in Science Advances, a team of Chinese researchers used mouse models to study the possibility of rejuvenating the immune system through bone marrow transplantation in young mice to slow immune aging and potentially use this as a therapeutic strategy against Alzheimer's disease.

More and more research points to the role of immune system dysfunction in the pathogenesis of Alzheimer's disease. It has been observed that about 50% of the genes associated with Alzheimer's disease, such as BIN1 (encoding adapter protein 1), CD33 (encoding myeloid surface antigen) and receptor expressed on myeloid cells 2 (TREM2), are involved in immune system processes.

Age-related decline in immune system function results in decreased production of immune cells, decreased diversity of the immune repertoire, and accumulation of dysfunctional immune cells—a phenomenon known as immune senescence. Immune senescence is thought to be a driver of systemic aging, including brain aging, and increases susceptibility to age-related degenerative diseases such as Alzheimer's disease. Therefore, it can be assumed that rejuvenation of immune cells may have a positive effect on slowing the progression of Alzheimer's disease.

In the present study, the researchers used nine-month-old transgenic Alzheimer's disease mice and transplanted bone marrow into them from younger (two-month-old) Alzheimer's disease mice. In the control group, mice were transplanted with bone marrow from similar nine-month-old mice.

Researchers have suggested that hematopoietic stem cells, which give rise to peripheral immune cells, in the bone marrow of young mice may rejuvenate aging immune cells and provide a potential therapeutic strategy against Alzheimer's disease. Peripheral blood mononuclear cells (PBMCs) were characterized to determine changes in gene expression of peripheral immune cells.

Studies show that peripheral lymphohematopoietic cells are restored approximately three weeks after bone marrow transplantation. Therefore, the researchers assumed that the anti-Alzheimer's effects would take place after three weeks, and they conducted behavioral tests such as the Y-maze and open field tests to assess brain function.

PBMCs were analyzed to evaluate the effects of old and young bone marrow on immune cell composition in mice. The proportions of B cells, T helper cells, cytotoxic T cells, monocytes, macrophages, dendritic cells, neutrophils, basophils and natural killer cells were determined.

In addition, tests such as amyloid β phagocytosis and cellular debris phagocytosis were performed to evaluate monocyte function. Brain sections from euthanized mice were stained for immunochemical analysis and immunohistochemistry tests. Brain sections were stained for amyloid β plaques and neurodegeneration based on neuronal apoptosis and neurite loss and degeneration.

Brain sections were also used for brain volume analysis and Western blotting to detect amyloid β and complete amyloid precursor protein. Inflammatory factors such as interleukin-10, interferon-γ and tumor necrosis factor-α were assessed using enzyme-linked immunosorbent assay method.

Total ribonucleic acid (RNA) extracted from monocytes was used for quantitative reverse transcription-polymerase chain reaction (qRT-PCR), while microglia were used for bulk RNA sequencing. In addition, the plasma proteome was assessed using liquid chromatography-tandem mass spectrometry.

Single cell-level RNA sequencing data were analyzed to identify cell types and for differential gene expression, transcription factor regulatory network analysis, cell communication assessment, and pathway enrichment.

The study found that transplantation of young bone marrow significantly reduced neurodegeneration, amyloid plaque burden and neuroinflammation, and improved behavioral deficits observed in an aged mouse model of Alzheimer's disease. Increased clearance of amyloid β also contributed to the improvement of cerebral amyloidosis.

Single-cell RNA sequencing data indicated that the expression of various genes associated with Alzheimer's disease and aging was restored in different types of immune cells after young bone marrow transplantation. Moreover, circulatory levels of secretory proteins associated with aging were lower after bone marrow transplantation.

The researchers found that among the differentially expressed genes associated with aging, Alzheimer's disease risk genes showed the highest expression in monocytes. Because circulating monocytes can clear amyloid β, age-related impairment of amyloid β phagocytosis by monocytes may accelerate plaque formation. Thus, rejuvenation of monocytes along with other immune cells through young bone marrow transplantation represents a promising therapeutic strategy.

In conclusion, the study results support the effectiveness of young bone marrow transplantation to rejuvenate senescent immune cells, which resulted in reduced neurodegeneration in a mouse model of Alzheimer's disease. Improved monocyte function resulted in increased clearance of amyloid β and decreased neuroinflammation.

Behavioral deficits observed in an aging mouse model of Alzheimer's disease also improved after bone marrow transplantation from young mice. Taken together, these results suggest that young bone marrow transplantation is a promising strategy for the treatment of Alzheimer's disease.