The Role of the Immune System in Neurodegeneration
Post by Andrew Vo
The takeaway
The immune system plays a potential role in neurodegenerative diseases, such as Lewy body dementia. The mechanism by which an inflammatory response is trafficked to the brains of these patients might be a potential therapeutic target.
What's the science?
Lewy body dementia (LBD) is distinguished by the abnormal accumulation of α-synuclein protein in the brain, leading to changes in the memory and behavior of these patients. Animal studies have suggested a role of the immune system in LBD, although the mechanism by which T cells (specialized cells in our bodies that identify and attack substances with foreign “antigens” or markers) migrate and function in the brain remains unknown. This week in Science, Gate et al. examine biological samples collected from living and postmortem patients to investigate the relationship between immunity-related T cells and LBD pathology.
How did they do it?
The authors first compared cognitive function and cerebrospinal fluid (CSF) levels of neurofilament light chain (a protein marker of neurodegeneration) in LBD patients and healthy controls. To directly test if the immune system interacted with LDB pathology, they then examined postmortem brains of LBD patients for T cell localization with α-synuclein accumulation. Next, they used sequencing analyses to measure T cell binding molecules, namely CXCR4 and CXCL12, in the CSF and meninges (protective membranes inside the skull and surrounding the brain) of LBD patients. Finally, they measured T cell immune activation in CSF samples from LBD patients through stimulation with a pool of peptide proteins derived from α-synuclein.
What did they find?
DLB patients were found to have reduced cognitive function and increased neurofilament light chain levels in their CSF. Examining postmortem brains, T cells were observed to be localized next to α-synuclein deposits and were mostly concentrated near the substantia nigra (a brain region containing dopamine neurons that degenerate in Parkinson’s disease) in LBD patients. This demonstrated a link between the immune system and brain pathology in LBD.
Sequencing of T cells in the CSF revealed greater expression of CXCR4 and CXCL12 markers in LBD patients compared to controls. A similar pattern was found in the meninges of LBD patients and specifically localized to the brain’s vasculature (or blood supply). Increased CXCL12 levels measured in CSF were related to lower cognitive function and higher neurofilament light chain levels. Together, these results show that increased CXCR4-CXCL12 signaling is associated with neurodegeneration in LBD.
Before stimulation with a peptide pool containing proteins derived from α-synuclein, T cells in the CSF showed greater baseline activation in LBD patients versus controls. This immune activation was further enhanced following peptide stimulation. Sequencing of these stimulated cells showed increased expression of interleukin 17A, which is related to inflammatory responses mediated by TH17 cells. Examining postmortem brains, they found T cells localized near TH17 cells in the substantia nigra of LBD patients. These findings suggest the involvement of TH17 cells and immunoreactivity in LBD neurodegeneration.
What's the impact?
In summary, this study demonstrated a link between the immune system, specifically CXCR4-CXCL12 signaling that recruits T cells to the brain, and neurodegeneration in LBD. The authors highlight a pathological mechanism in human patients that was previously only established in animal models of neurodegeneration. This signaling mechanism may be a potential therapeutic target for the treatment of LBD.