- The aggregation of the beta-amyloid protein into insoluble deposits in the brain is a hallmark of Alzheimer’s disease.
- A recent study shows that replacing blood in a mouse model of Alzheimer’s disease with blood from healthy wild-type mice could slow down the formation of beta-amyloid deposits.
- This blood exchange treatment also improved spatial memory in the Alzheimer’s disease mouse model.
- The study could facilitate the development of novel treatments for Alzheimer’s disease that target proteins or other factors in the blood.
A new study published in
Although the mechanisms underlying these findings remain unclear, the results suggest that manipulating certain components in the blood could help treat AD.
Targeting components in the blood for the treatment of AD can help bypass the challenges associated with developing drugs that can cross the blood-brain barrier.
AD is the most common form of
A central characteristic of AD is the abnormal accumulation of the beta-amyloid protein into deposits, known as plaques, in the brain.
Single units, or monomers, of the beta-amyloid protein tend to aggregate together to form short chains called oligomers. These soluble oligomers aggregate to form fibrils, which later form insoluble plaques. Experts consider these beta-amyloid aggregates to be responsible for the damage to brain cells in AD.
Beta-amyloidmonomers are produced in the brain and also in other organs. Beta-amyloid monomers and oligomers can cross the blood-brain barrier, passing from the brain to the blood and from the blood to the brain. The beta-amyloid protein is broken down in
In contrast, isolating the beta-amyloid protein in the blood using antibodies that cannot cross the blood-brain barrier can
Similarly, surgically connecting the blood circulation of a wild-type mouse with that of a transgenic AD mouse model can
These data suggest that beta-amyloid protein levels in the blood could impact the levels of beta-amyloid deposits in the brain. Thus, treatments that lower beta-amyloid levels in the blood circulation could be used to slow down the progression of AD.
In the present study, the researchers examined whether the partial replacement of the blood of a transgenic mouse model of AD with the blood of wild-type mice could reduce the levels of beta-amyloid in the brain of the mouse model.
During the blood exchange treatment, the researchers withdrew 40-60% of the blood from the transgenic mice and replaced the withdrawn blood with blood from healthy wild-type mice.
They started this blood exchange treatment when the transgenic mice were 3 months old — which means they were mature adults — and before the onset of the formation of beta-amyloid plaques.
This blood exchange procedure was performed once a month for the next 10 months until the mice were 13 months old, or middle-aged.
Unlike the untreated transgenic mice that showed beta-amyloid plaques at 13, the transgenic mice receiving the blood exchange treatment showed fewer plaques and a lower plaque burden, which is a measure of the area of the brain covered by plaques.
The researchers also assessed the impact of the blood transfusions from wild-type mice on the memory of the transgenic AD mouse models at 12.5 months of age.
The transgenic mice from the blood exchange group performed better in short-term and long-term spatial memory tests than untreated transgenic mice. Furthermore, the performance of the mice in the blood exchange group was similar to wild-type mice.
In a similar experiment, the researchers continued the monthly blood exchange procedure until 17 months of age. They used the data from the mice sacrificed at 13 and 17 months of age to assess the rate of plaque growth during this period.
The researchers thus found that the blood exchange treatment slowed down the rate of plaque growth.
In the first set of experiments, the researchers started the blood exchange procedure in 3-month-old mice before the development of beta-amyloid plaques.
To examine the potential of this procedure for the treatment of AD, the researchers started the monthly blood exchange treatment at 13 months when transgenic mice tend to show beta-amyloid deposits in the brain and memory deficits.
The researchers found that transgenic mice receiving blood exchange treatment showed fewer beta-amyloid plaques and lower plaque burden at 17 months of age than age-matched untreated transgenic mice.
Moreover, the plaque burden in the 17-month-old transgenic mice receiving the blood exchange treatment was similar to untreated transgenic mice at 13 months. These results suggest that the blood exchange treatment prevented further accumulation of beta-amyloid plaques.
Notably, the performance of the transgenic mice in the blood exchange treatment group in the spatial memory tests was similar to age-matched wild-type mice and better than age-matched untreated transgenic mice.
These experiments show that blood exchange could serve as a disease-modifying treatment, which delays or halts the progression of AD.
The researchers found that beta-amyloid levels in the blood of the transgenic mice increased soon after the blood transfusion from wild-type mice.
Thus, it is possible that the lowering of blood beta-amyloid levels upon the introduction of blood from wild-type mice could enhance the transfer of beta-amyloid from the brain to the bloodstream. This might be a mechanism for the decline in brain beta-amyloid levels due to the blood exchange procedure.
However, the researchers did not directly remove beta-amyloid from the blood of the transgenic AD mouse model and other proteins or factors in the blood could also explain these results.
Thus, more research is needed to characterize the blood components and pinpoint the mechanisms underlying the impact of the blood exchange treatment on memory and beta-amyloid plaques.
The characterization of the blood components underlying these effects of the blood exchange treatment could facilitate the development of treatments for AD patients.
The study’s lead author, Dr. Claudio Soto, a neurology professor with McGovern Medical School at UTHealth Houston, told Medical News Today that procedures such as plasmapheresis and
Dr. Soto noted that “[s]tudies in mouse models are necessary as a first step to analyze the efficacy of a therapeutic strategy. Of course,” he added, “mice are not humans, so we would need to show that our approach works in ‘real life’ with ‘real patients.’”
“Whole blood exchange — as we did in this study — is not feasible in humans [as such], but there are two technologies currently in common medical practice that may work: plasmapheresis and blood dialysis. We are currently adapting these techniques for mice studies and if we obtain positive results, the next step will be to start some clinical trials in humans affected by AD.”
– Dr. Claudio Soto
We also spoke with Dr. Erik S. Musiek, a professor of neurology at Washington University School of Medicine in St. Louis, who was not involved in this study.
Commenting on the study, Dr. Musiek noted: “The authors focus on the idea that there is a pool of beta-amyloid in the periphery that is in equilibrium with that in the brain, and that adding blood with minimal beta-amyloid creates a sink by which beta-amyloid transfers from the brain to the blood, limiting plaque formation. This peripheral sink hypothesis has been around for a long time and has been demonstrated in mice after [the] administration of Abeta antibodies.”
“However, there are likely many other possible mechanisms at play here,” he cautioned. Moreover, according to Dr Musiek, “[t]he fact that the blood donors are young, while the AD model mice receiving the blood get quite old (13 months), suggests that there may be factors in the young blood which directly limit beta-amyloid pathology and promote cognition.”
“It is also possible that the fresh, young blood alters the immune response in the brain of the recipients, facilitating beta-amyloid metabolism” Dr. Musiek hypothesized. “Finally, it remains unclear if blood exchange in mice that already have [a] significant plaque burden can enhance [the] removal of plaques, as opposed to [preventing] their initial accumulation.”
“This is very important, as we generally identify people with preclinical AD based on the fact that they already have plaques, and primary prevention therapies to prevent that gradual plaque accumulation are very difficult to implement in humans. However, this study certainly reveals a very interesting phenomenon and should inspire future research,” said Dr. Musiek.
Read the full article here