A mouse experiment suggested familial Alzheimer’s disease may be transmitted through bone marrow stem cells, but the implications of the findings were limited.
The research involved transplanting bone marrow stem cells from mice engineered to carry a familial Alzheimer’s disease mutation into healthy mice, which led to “rapid development of Alzheimer’s disease pathological hallmarks,” reported Wilfred Jefferies, DPhil, of the University of British Columbia in Vancouver, and co-authors.
“These pathological features were significantly accelerated and emerged within 6-9 months post transplantation and included compromised blood-brain barrier integrity, heightened cerebral vascular neoangiogenesis, elevated brain-associated β-amyloid levels, and cognitive impairment,” Jefferies and colleagues wrote in Stem Cell Reports.
The findings provided “conclusive demonstration of iatrogenic Alzheimer’s disease transmission in a model of stem cell transplantation,” the researchers noted in the title of their paper.
But Alzheimer’s experts didn’t see it that way. “The claim in the title is not supported by the data,” Bart De Strooper, MD, PhD, of University College London, told MedPage Today.
“There is, however, other evidence that amyloid — and tau, by the way — can be transmitted from person to person in exceptional conditions,” De Strooper said. While this appears to not be a major concern for public health, “further research is certainly needed and vigilance is recommended,” he added.
On the U.K. Science Media Centre, Tara Spires-Jones, DPhil, of the University of Edinburgh in Scotland, listed the study’s limitations.
“The recipient mice did not develop Alzheimer’s disease, they had small amounts of pathology and memory deficits in small groups of animals. They did not have neurodegeneration or tau pathology which occur in Alzheimer’s disease,” she posted.
“While other data in the field do support the idea that amyloid pathology ‘seeds’ can induce clumping in healthy brain, there has never been conclusive evidence that this leads to dementia,” Spires-Jones noted.
For example, five patients treated with human growth hormone from cadaveric pituitary glands when they were children subsequently developed cognitive or biomarker changes consistent with Alzheimer’s disease, but whether amyloid seeding led to dementia in these cases was unknown.
In their experiment, Jefferies and colleagues transplanted donor bone marrow stem cells carrying a mutant human amyloid precursor protein (APP) transgene into either APP-deficient knockout or normal mice. Recipient mice had whole-body radiation before the transfer.
Pathology and behavior changes occurred in both groups of mice and suggested the transferred bone marrow cells had delivered the mutant gene in a form that could drive brain disease, the researchers noted.
“Consequently, our observations advocate for genomic sequencing of donor specimens prior to tissue, organ, or stem cell transplantation therapies, as well as blood transfusions and blood-derived product administration, to mitigate the risk of iatrogenic diseases,” Jefferies and co-authors wrote.
“The fact that bone marrow cells could be sufficient to induce amyloid pathology in the brain is surprising, as current evidence suggests that the amyloid accumulation in the brain of people with Alzheimer’s originates from neurons and supporting glial cells,” De Strooper observed.
“This paper could be of great interest; however, the data supporting the claims are too limited to make final conclusions,” he said.
“There are a number of issues with the analysis; for instance, the quantitative assessment of the amyloid-beta levels in the brains of the transplanted animals is missing,” De Strooper noted. Other results are unclear or not of good enough quality to be convincing, he added. “There is not sufficient evidence here to suggest that anyone receiving a bone marrow transplant is at risk of developing Alzheimer’s disease as a result of the procedure, and nobody should forego a transplant for this reason.”
On the Science Media Centre site, Sheona Scales, PhD, director of research at Alzheimer’s Research U.K., posted that “much more research is needed to understand whether this process is ever likely to occur in people.”
“It is important to note that these experiments were done in mice engineered to carry a rare genetic mutation, which accounts for an extremely small number of Alzheimer’s cases in people,” Scales said.
“And while animal research can give valuable clues into how the diseases that cause dementia start and develop, there are key biological differences between mice and people,” she added. “It is not clear that this mechanism is relevant outside of a laboratory experiment.”
Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow
Disclosures
This research was supported by the Canadian Institutes of Health Research, the W. Garfield Weston Foundation/Weston Brain Institute, the Centre for Blood Research, the University of British Columbia, the Austrian Academy of Science, and the Sullivan Urology Foundation at Vancouver General Hospital.
The researchers hold equity in Cava Healthcare, a start-up company that possesses intellectual property related to the study findings.
De Strooper reported no direct conflicts of interest with the study, but said he was a consultant of several pharmaceutical companies working on Alzheimer’s disease.
Spires-Jones had no conflicts.
Primary Source
Stem Cell Reports
Source Reference: Singh CSB, et al “Conclusive demonstration of iatrogenic Alzheimer’s disease transmission in a model of stem cell transplantation” Stem Cell Rep 2024; DOI: 10.1016/j.stemcr.2024.02.012.
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