While neurons have been classically the major focus of research into Alzheimer's disease, a new study has revealed that the immune system plays a crucial and previously unidentified role in the neurodegenerative disorder.
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A new study has found evidence that demonstrates the role of a subpopulation of cells belonging to the adaptive system in Alzheimer's disease. Scientists believe that these findings will be significant in deepening our understanding of the underlying mechanisms that support Alzheimer's and allow it to progress.
Subpopulation of immune cells found to be distinct to Alzheimer's disease
An international team of researchers from Stanford University and Paracelsus Medical University, Salzburg, Austria, published results of their ground-breaking study this week in the journal Nature. The researchers compared immune cells taken from blood samples collected from a group of healthy participants against immune cells extracted from blood samples taken from participants with Alzheimer's disease or mild cognitive impairment (MCI), a precursor of the disease.
The team was able to identify the presence of a certain group of cells, known as CD8+ T effector memory CD45RA+ (TEMRA) cells, in the samples taken from those with Alzheimer's disease and MCI, but not it the healthy population. Interestingly, previous studies have identified TEMRA as being cell-death-promoting through their initiation of the release of inflammatory and cytotoxic molecules.
Cause or effect?
Further analysis further hinted at the role of TEMRA cells in Alzheimer's, with researchers finding a higher incidence of these cells in a separate cohort of people with Alzheimer's disease who had lower levels of cognitive function.
These results suggest that the existence of TEMRA cells may disrupt normal cognitive functioning, and might be a causal factor for the cognitive decline that characterizes the neurodegenerative disease. Researchers speculate that this neuronal dysfunction may be a result of the TEMRA cells secreting inflammatory and cytotoxic molecules in the brain.
On the other hand, increased levels of TEMRA cells may be an effect of a damaged neural mechanism that causes cognitive dysfunction and triggers the release of TEMRA cells as an immune response to the damaged system.
TEMRA cells can accurately predict disease status
The researchers then sought to find out whether the presence of TEMRA cells could effectively predict disease status. They were able to show that a machine-learning algorithm could successfully take the measurements of TEMRA cells to accurately (80% accuracy) determine the disease status of the participant.
Usually, immune processes change with aging and therefore, can not be used for predictive clinical testing. However, the study showed that age did not significantly impact on the levels of TEMRA cells. This is exciting because it could be potentially used alongside other established tests to identify Alzheimer's at its early stages.
Furthermore, the team looked closely at the brains of those in the group who had died with Alzheimer's disease. Their investigations concluded that TEMRA cells might be the cause of neuronal damage, rather than the effect of it, through the secretion of immune molecules as well as by directly damaging neuronal processes.
Finally, the team discovered that TEMRA cells are the predominantly expanded T-cell clone in those with Alzheimer's disease. Following this discovery, researchers then asked the question of which antigens are responsible for driving the clonal expansion of TEMRA cells. By looking at TCR sequences in those with MCI and Alzheimer's disease, the investigators were able to determine that two antigens produced by the Epstein–Barr virus (EBV) were responsible for clonally expanded TEMRA cells.
However, due to the fact that this virus is not suggested to be involved in the development of Alzheimer's, the small sample size of the study is not sufficient to determine this, and data should be carefully interpreted at this stage.
Gate, D. et al. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. DOI: https://doi.org/10.1038/s41586-019-1895-7