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

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

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

Age-related decline in immune function results in decreased immune cell production, 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. It is therefore conceivable that rejuvenation of immune cells may have a positive effect on slowing the progression of Alzheimer’s disease.

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

The researchers hypothesized that hematopoietic stem cells, which give rise to peripheral immune cells, in the bone marrow of young mice could rejuvenate senescent 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 recover approximately three weeks after bone marrow transplantation. Therefore, the researchers hypothesized that the anti-Alzheimer effects would be evident 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 assess the effect 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 for amyloid β and total amyloid precursor protein. Inflammatory factors such as interleukin-10, interferon-γ, and tumor necrosis factor-α were assessed using enzyme immunoassay.

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. Additionally, plasma proteome was assessed using liquid chromatography-tandem mass spectrometry.

Single-cell RNA-seq data were analyzed for cell type identification and differential gene expression, transcription factor regulatory network analysis, cellular communication assessment, and pathway enrichment.

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

Single-cell RNA sequencing data indicated that expression of various genes associated with Alzheimer's disease and aging was restored in different immune cell types after young bone marrow transplantation. Moreover, circulating levels of aging-related secretory proteins 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. Since 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 results of the study support the efficacy of young bone marrow transplantation in rejuvenating senescent immune cells, which resulted in reduced neurodegeneration in a mouse model of Alzheimer's disease. Improved monocyte function resulted in increased amyloid β clearance and reduced neuroinflammation.

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