As living standards increase and health provisions become better and more accessible to all, we can look forward to living longer. Yet one of the biggest medical challenges today is to achieve old age in good mental health. Because what is the point of being 80 or 90 if your mental capacities resemble that of a toddler, or if your brain is no longer able to tell your body to move?
Degenerative diseases such as Alzheimer, Parkinson’s disease, multiple system atrophy or amyotrophic lateral sclerosis affect, sooner or later, a large percentage of the elderly, with an average onset of disease in the mid-sixties. Yet the cause of these diseases is unclear, even if we know that there are some genes that make an individual prone to develop them.
The working hypothesis is that with age, our neurons become weak and specific proteins start accumulating, inducing atrophy and neuronal death. In the case of Parkinson disease and multiple system atrophy, the protein involved is alpha-synuclein. Due to an unknown failure, this protein aggregates and gets modified inside the neurons, rendering them dysfunctional and eventually resulting in their death. These processes make a group of small cells in-charged of assuring the well being of the neurons (microglia) to produce a range of molecules that cause brain inflammation, resulting in a vicious cycle of brain damage.
Microglia are known to act as the brain’s immune system, and until recently it was thought that the peripheral immune system did not interact with the brain at all. However, in the last 10 years, it has become increasingly evident that there is a direct interaction between the brain and the peripheral immune system. It has been shown in brains from Parkinson’s disease patients that adaptive immune cells (T cells) permeate the brain during disease and that antibodies deposit on neurons. Indeed there are antibodies against alpha-synuclein in the blood of Parkinson disease patients.
From animal models of Parkinson’s disease, where alpha-synuclein is made to accumulate in neurons to induce their death, we know that both the peripheral (T cells/antibodies) and resident (microglia) immune system are able to react specifically to the different stages of alpha-synuclein-induced pathology.
However, it is not known if the peripheral immune system is activated as a consequence of the disease or if it is also affected during the disease, thus contributing directly to it. This is a very pertinent question as immune cells, in particular, T cells, produce alpha-synuclein themselves and alpha-synuclein also accumulates in peripheral tissue.
A research group from Aarhus University (Denmark) recently published an article in Heliyonaddressing this question. They locally increased alpha-synuclein in the periphery of healthy mice (not in brain) and followed the adaptive immune response (CD4 T cells and antibody generation). They found that there were fewer CD4 T cells, but those T cells in-charged of regulating the immune cells (memory Foxp3+ regulatory T cells) were increased in number, showing that the peripheral immune system reacted to alpha-synuclein.
This led the research group to wonder if the peripheral immune system would react differently when confronted with a modified form of alpha-synuclein, the type that is found during Parkinson’s disease (long filaments of aggregated alpha-synuclein and nitrated alpha-synuclein). They found that indeed it did! When alpha-synuclein is present as filaments, the number of regulatory T cells is increased and antibodies against alpha-synuclein are induced, while when alpha-synuclein is nitrated more T cells were produced. This was very interesting since alpha-synuclein filaments are thought not to induce neuronal death and nitrated to be very toxic.
When Olesen at al. looked at the brains of these mice, they found that T cells had reached the brains and, even if the neurons were not affected, microglia had acquired specific characteristics depending on the alpha-synuclein that had been present in the periphery, giving them in each case particular abilities to react to processes in the brain.
The authors concluded that the adaptive immune system was able to sense local changes to alpha-synuclein concentration in an alpha-synuclein variant-dependent manner, inducing specific modulation of the CD4+ T cell pool, antibody production, and microglia phenotype. Hence, how the peripheral adaptive immune system is modulated by alpha-synuclein has direct consequences for brain microglia and how it can react to brain pathology. These results open the door to the idea of modulating the peripheral adaptive immune system to change how microglia, the brain immune system, behave during Parkinson’s disease. One could, for instance, prevent microglia from inducing brain inflammation and instead make it produce factors that will help the sick neurons handle the increased accumulation of alpha-synuclein.
These findings are described in the article entitled CD4 T cells react to local increase of α-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology, recently published in the journal Heliyon. This work was conducted by Mads N. Olesen, Josefine R. Christiansen, Steen Vang Petersen, Poul Henning Jensen, Wojciech Paslawski, Marina Romero-Ramos, and Vanesa Sanchez-Guajardo from Aarhus University.
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