This story is part 9 of an occasional series on the current progression in Regenerative Medicine. In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.
A recent study led by researchers at Stanford School of Medicine has discovered that blood transfusions from highly active mice into same-aged, sedentary mice boosted brain function in the sedentary recipients. This discovery may mark a significant step in uncovering effective treatments to slow the progression of neurodegenerative diseases like Alzheimer’s or Dementia.
It is known that exercise has a myriad of benefits, particularly when it comes to slowing cognitive aging and limiting the progression of neurodegenerative diseases. Past studies have shown that the progression of neurodegenerative diseases is linked to inflammation of the brain and that exercise can reduce this inflammation. This study demonstrates that the positive effects of exercise on the brain may be transferable to individuals who are not as active through simple blood plasma transfusions.
The Stanford team based their experiments on the fact that mice love to run. When a mouse has access to a running wheel, it can run up to 4 to 6 miles within a single night, unprompted. If the running wheel is locked, the mouse will be reduced to sedentary exercise, simply skittering around its cage.
The team placed 3-month-old mice (3-month-old mice are metabolically equivalent to 25-year-old humans), into cages that either had functional or locked running wheels. After a month of steady running by mice with functional wheels, these marathoner mice exhibited substantially increased quantities of neurons and other cells in the brain compared to the sedentary mice.
Scientists then collected blood from the marathoner mice along with blood from sedentary mice as a control and injected the sedentary mice with either type of blood. The mice were specifically injected with blood plasma, the cell-free portion of blood. They repeated these blood transfusions every three days.
Surprisingly, the sedentary mice that received blood transfusions from the marathoner mice exhibited a significant increase in the number of cells responsible for producing new neurons compared to mice that received blood transfusions from other sedentary mice. They also exhibited lower levels of neuroinflammation. In behavioral tests, the mice given plasma from marathoner mice also outperformed their control group peers in memory-related tasks.
After confirming that exercise did in fact have a relationship to higher neural function and that these effects seemed to be transferable through blood plasma, the Stanford team then delved into the question of why? The marathoner mice seemed to have 235 distinct proteins, 23 of which were scarcer and 26 were more abundant in marathoner mice than their sedentary peers. An intriguing aspect of these proteins was that many of them seemed to be related to the proteins responsible for inducing immune responses.
There was one protein of particular interest—clusterin. Clusterin is an inhibitor of the immune response and was significantly more abundant in marathoner mice blood than their sedentary counterparts. In addition, when researchers removed clusterin from the plasma of marathoner mice before transfusions, the anti-inflammatory effect of these transfusions was largely negated. There was no other protein related to the immune response that seemed to have as significant a role as clusterin in decreasing brain inflammation in sedentary mice.
To further establish this link between clusterin and neuroinflammation, the Stanford team induced lab mice with either acute body-wide inflammation or chronic neuroinflammation that replicated Alzheimer’s. After administering clusterin by itself, the protein was able to significantly reduce brain inflammation in both strains of lab mice.
Clusterin is an intriguing protein. It exists in three forms: one isoform is located in the cell nucleus, a second isoform is found in the cytoplasm of the cell, and the third form of the protein is secreted from the cell. Interestingly, the isoforms of clusterin have opposing functions. While one isoform promotes cell death, the other two isoforms inhibit cell death. These contradictory roles have made clusterin a highly enigmatic protein whose role is not completely understood. In fact, several studies have found that the presence of certain clusterin isoforms was related to faster cognitive decline in individuals with Alzheimer’s disease—contrary to the conclusions of this recent study. Furthermore, clusterin may play a role in the growth of cancer cells and tumors.
While the authors of the Stanford study suggest that a drug that can enhance or mimic the activities of clusterin may slow the course of neurodegenerative diseases, more research must be conducted to determine the functions of each clusterin isoform in Alzheimer’s progression to piece together which exact form of the protein may be beneficial and can be used as a treatment for these diseases.
Overall, this study is an intriguing one that marks significant progress in isolating the biological causes of neuroinflammation and may open new windows for the treatment of neurodegenerative diseases.