A recent study published in Stem Cell Reports suggests that familial Alzheimer's disease (FAD) could potentially spread through bone marrow transplantation. Researchers found that when bone marrow stem cells from mice with genetic mutations causing FAD were transplanted into normal mice, the recipients developed Alzheimer's disease at an accelerated rate.
Research Illustration (Excerpt from Paper)
This research underscores the role of amyloid-beta proteins originating from outside the brain in the development of Alzheimer's disease, shifting Alzheimer's from a disease solely produced in the brain to a systemic one. Researchers suggest that donors of blood, tissues, organs, and stem cells should undergo screening for Alzheimer's disease to prevent inadvertent transmission during blood transfusions and cell therapies.
"This supports the notion that Alzheimer's is a systemic disease, where amyloid-beta proteins expressed outside the brain lead to central nervous system pathology," said Wilfred Jefferies, immunologist at the University of British Columbia, and the corresponding author of the paper. "As we delve deeper, Alzheimer's may just be the tip of the iceberg, necessitating better control and screening of donors involved in blood, organ, and tissue transplants as well as human stem cell or blood product donations."
To test whether externally sourced amyloid-beta proteins affect Alzheimer's development in the brain, researchers transplanted bone marrow from mice carrying a familial form of Alzheimer's disease, a variant of the human amyloid precursor protein (APP) gene that, when cleaved, misfolded, and aggregated, forms amyloid plaques, a hallmark of Alzheimer's. They transplanted into two different recipient mice strains: one lacking the APP gene entirely (APP knockout mice) and the other carrying the normal APP gene.
In the genetic model of familial Alzheimer's disease, mice typically begin to show plaques at 9 to 10 months old, with behavioral signs of cognitive decline emerging at 11 to 12 months. Surprisingly, transplant recipients exhibited cognitive decline much earlier—APP knockout mice at 6 months post-transplantation, and normal mice at 9 months post-transplantation.
"We observed significant behavioral differences and cognitive decline in the APP knockout group within 6 months, which was surprising but also intriguing as it indicates an accelerated onset of the disease post-transplantation," said Chaahat Singh, the first author of the paper from the University of British Columbia.
In mice, cognitive decline manifests as lack of normal fear responses and loss of both short-term and long-term memory. Both recipient groups also exhibited distinct molecular and cellular features of Alzheimer's, including blood-brain barrier leakage and accumulation of amyloid-beta in the brain.
By observing disease transfer in APP knockout mice, the research group concluded that mutations in donor cells lead to the disease, with recipient animals carrying the normal APP gene being susceptible, suggesting the disease can be transmitted to healthy individuals.
Since transplanted stem cells are hematopoietic, meaning they can develop into blood and immune cells but not neurons, the presence of amyloid-beta in the brains of APP knockout mice found by researchers suggests that Alzheimer's may be caused by amyloid-beta originating outside the central nervous system.
Lastly, the disease source in the mouse model is the human APP gene, indicating that mutated human genes can transfer disease across different species.
In future research, the team plans to test whether transplanting tissues from normal mice onto those with familial Alzheimer's disease can ameliorate the disease and whether the disease can also spread through other types of transplants or blood transfusions, broadening the scope of species transfer studies.
"In this study, we analyzed bone marrow and stem cell transplants. It's crucial next to examine if other forms of cell therapies also experience inadvertent disease transmission and directly test the transfer of diseases from contaminated sources independent of cellular mechanisms," Jefferies said.
For more information on the paper, please visit: https://doi.org/10.1016/j.stemcr.2024.02.012
