Transmission of Alzheimer’s Disease Pathology through Bone Marrow Transplantation in a Preclinical Model

Iatrogenic transmission refers to the unintended spread of a disease due to medical procedures or treatments. The concept of iatrogenic transmission in relation to Alzheimer’s disease (AD) involves a very specific and controversial hypothesis that certain medical procedures might theoretically spread amyloid-β (Aβ) proteins, which are associated with Alzheimer’s disease, from an affected individual to a healthy one, potentially increasing the latter’s risk of developing the disease. AD is characterized by the accumulation of Aβ plaques and tau protein tangles in the brain, leading to neurodegeneration and cognitive decline. The hypothesis of iatrogenic transmission emerged from observations similar to those seen in prion diseases, such as Creutzfeldt-Jakob Disease, where abnormal protein structures can be transmitted between individuals through certain medical procedures, leading to disease.  Till now there is no definitive evidence to confirm the iatrogenic transmission of AD in humans through medical procedures. Nonetheless, this area remains of interest for further research, particularly with advances in our understanding of how Aβ and tau proteins behave and interact within the body. The hypothetical risk of iatrogenic transmission of AD  has led to recommendations for increased caution and the use of enhanced sterilization techniques for surgical instruments, especially in neurosurgery. It has also prompted a reevaluation of the safety protocols surrounding organ transplantation and the administration of treatments derived from human tissues. To this end, a new study published in Stem Cell Reports Journal and composed of Chaahat Singh, Kelly Marie Johns, Suresh Kari, Lonna Munro, Angela Mathews, Franz Fenninger, Cheryl Pfeifer, and led by Professor Wilfred Jefferies from the University of British Columbia, the authors investigated the transmission of AD pathology through bone marrow stem cell transplantation.

To investigate whether AD pathology could be transmitted through bone marrow transplantation, the researchers used donor bone marrow stem cells carrying a mutant human amyloid precursor protein (APP) transgene. These were transplanted into two types of recipient mice: APP-deficient knockout mice and normal wild-type (WT) mice. They used transgenic mice (referred to as AD mice), which express a Swedish mutant form of human APP, known for its association with familial AD. The control group comprised their WT littermates. The recipient groups included APP knockout mice, lacking the endogenous mouse APP gene, and WT mice to assess the effects of the transplanted cells. Following irradiation to deplete their existing bone marrow, recipient mice were transplanted with bone marrow cells from either AD or WT mice. The efficiency of transplantation was verified using markers to distinguish donor from recipient cells.

The authors observed successful engraftment with a significant presence of donor-derived cells in the recipient mice, indicating that the transplantation process was effective. The team assessed the development of AD pathology through several parameters, including blood-brain barrier integrity, cerebral vascular neoangiogenesis, β-amyloid levels in the brain, and cognitive function. They found that recipient mice exhibited rapid development of AD pathological hallmarks within 6–9 months post-transplantation. This included compromised blood-brain barrier, increased neoangiogenesis, elevated β-amyloid levels, and cognitive deficits, closely mirroring the pathology seen in AD. To evaluate the impact of the transplanted AD pathology on cognitive function, researchers conducted a series of behavioral tests, including open-field tests, Y maze, and fear conditioning and found mice receiving AD bone marrow showed significant cognitive impairments and behavioral changes compared to controls. This was indicative of AD-like pathology affecting their cognitive abilities. Moreover, detailed molecular and histological analyses were performed to identify AD-specific markers in the recipient mice, focusing on β-amyloid deposits and vascular changes in the brain and found significant increases in β-amyloid levels and vascular abnormalities were observed in the brains of recipient mice, especially in those receiving AD bone marrow. This confirmed the transfer of AD pathology. Additionally, the study explored the role of β-amyloid produced outside the CNS, particularly from the transplanted bone marrow cells, in contributing to AD pathology within the brain and the results suggested that peripheral sources of β-amyloid, such as those arising from the transplanted bone marrow cells, can contribute to AD pathology in the CNS.

Given these findings, the study emphasizes the need for genomic sequencing of donor specimens before transplantation procedures. This is proposed as a preventive measure to mitigate the risk of transmitting AD and potentially other iatrogenic diseases, thereby enhancing the safety of organ and stem cell transplantation practices. The mechanism of AD transmission demonstrated in this study involves the adoptive transfer of bone marrow stem cells that carry a pathogenic mutant allele, leading to the recipient’s rapid development of AD pathology. This suggests a direct link between the mutant human APP transgene in donor cells and AD pathology in recipients, underlining the potent pathogenic role of β-amyloid produced by these transplanted cells. The study also sheds light on the pro-angiogenic signal provided by Aβ, facilitating its entrance into the brain through disrupted blood-brain barriers and contributing to the disease’s neuropathology. This mechanism underscores the multifaceted impact of β-amyloid, not only as a hallmark of AD pathology but also as a mediator of vascular and barrier integrity dysfunctions that facilitate its own CNS infiltration and accumulation.

In conclusion, the research conducted by Professor Jefferies and his team provides compelling evidence of a transplantable form of AD, highlighting the rapid onset of AD pathology in recipient mice following bone marrow transplantation from AD mice. The findings highlight the potential risks associated with transplanting cells or tissues from donors carrying pathological alleles, such as those related to AD. These results call for a reevaluation of donor screening processes, particularly the necessity for genomic sequencing, to mitigate the risk of transmitting AD and possibly other neurodegenerative diseases through medical procedures involving tissue and organ transplants.