An old story
I would like to start my blog by telling you an old story…
It was a hot day in August 2008, when Tony Wyss-Coray sat in a conference room waiting for his lab’s weekly meeting to begin. Wyss-Coray, a professor of neurology at Stanford University, was leading a group of young researchers who studied brain cells degeneration. Sitting close to him was Saul Villeda, an emerging PhD student, who had spent the past year conducting research that aimed to understand how blood affects the brain. They thought that some molecules contained in blood might be able to reach the brain and cause detrimental changes.
The hypothesis was not as absurd as it might sound.
Villeda conducted pilot studies with mice: young mice received blood from old mice, and old mice received blood from young ones. Villeda wanted to see the effect on their brains. Something which could have never been done in a living human being.
And what did Villeda find? Well, neurons in brains of young mice receiving old blood were unable to be regenerated, the neurons started to die, and ultimately young mice brains shrunk and became less functional. A region called the hippocampus, crucial for the process of brain cell generation, or neurogenesis, was one of the first to deteriorate, causing damage to mice’s memories and ability to process new information. Villeda immediately interrogated himself: “Why is this happening? What is it that “old blood” contains that is different from “young blood”?” The answer was simple: inflammation.
Body inflammation is regulated by our immune system, the defensive response which protects us against threats, such as infections. Villeda found that some inflammatory proteins contained in the blood of old mice were responsible for the damage of brain cells of young mice. Most importantly, he found that young mice receiving old inflamed blood exhibited cognitive impairments, including memory and learning deficits, similar to those found in patients with neurodegenerative disorders, such as Alzheimer’s.
A new story
Now, you may wonder why I decided to tell you this story… well, interestingly enough Villeda’s findings could be of relevance for other types of brain and mental health conditions. Indeed, patients with neuropsychiatric disorders, like depression, are known to share similar inflammatory features with Alzheimer’s patients. Strikingly, at least a sub-group of depressed patients had a high level of inflammatory proteins in blood, a reduced number of new generated cells in the brain, and show cognitive impairments similar to those described above for patients with neurodegenerative conditions. This seems to suggest that in patients with depression, similarly to those with Alzheimer’s, blood inflammation is somehow involved in the changes occurring in the brain, and might also contribute to the development of the clinical symptoms of depression.
We decided to investigate this hypothesis, and for this purpose we collected blood samples from patients with Hepatitis C virus (HCV), who received the inflammatory protein interferon-alpha (IFN-α) as standard treatment for their HCV infection. Interestingly, up to 35% of patients receiving this immunotherapy develop depression, and that is why this clinical model has been used for years to study the effect of inflammation in the context of depression.
However, the exact brain mechanisms via which this happens are still unknown.
Using a research model made up of human brain cells (not mice!), we exposed cells to blood from patients with and without depression, and we counted the number of new brain cells generated.
Something which, again, could have never been done in a living human being!
And findings were quite striking!
From our investigations, recently published in the journal of Brain, Behavior and Immunity, we were able to demonstrate that blood from depressed patients can reduce the number of new generating brain neurons and increase the number of dying cells, when compared with blood from non-depressed patients.
As Villeda did for his study, we immediately interrogated ourselves: “Why is this happening? What is it that IFN-α is doing to make the blood of some patients “depressed”?”
The answer, again, was simple: inflammation.
Although we were not able to detect any differences in the same inflammatory proteins reported by Villeda, we identified a novel group of blood molecules, like Mitogen-Activated Protein Kinases (MAPKs) and c-Jun N-terminal Kinases (JNKs), which are known to modulate the immune response, and to be potentially involved in the regulation of brain cells generation.
Overall, this seems to suggest that depression, similar to other neurodegenerative disorders, is not an “all in the brain” condition, and that the complex inflammatory environment characterising our blood can affect the life and health of our brain cells, ultimately predisposing the individuals to the development of the symptoms associated with those pathologies.
Of course, the story is much more complicated and there might be other factors contained in blood that, together with inflammation, can exert such detrimental consequences on our brain cells. These include other molecules, also detected in the blood of patients with neuropsychiatric or neurodegenerative disorders such as depression and Alzheimer’s, and belonging to the oxidative stress response, like Nuclear factor erythroid 2-related factor 2 (Nrf2) and Fos Proto-Oncogene, AP-1 Transcription Factor Subunit (FOS), which are also known to negatively affect brain cells generation.
Although, evidence exists for other blood factors to regulate neurogenesis, ours and Villeda’s findings, unequivocally propose blood inflammation as among one of the major culprits.
This, in turn, can have a crucial impact for patient’s therapeutic approaches.
If we manage to develop new drugs targeting those blood factors, we might be able to prevent brain cells degeneration and ultimately improve patients’ symptoms. Currently, molecules that block the action of specific inflammatory proteins have been tested in clinical trials for depression (see, for example, ClinicalTrials.gov identifier NCT02473289), or as antiviral strategy, which could be re-purposed for psychiatric indication.
One day, these new therapeutic interventions might become effective antidepressants, and will be prescribed to those patients having high levels of inflammation.
Header image source: lightsource