Microglia and beyond
Authors:   , van Olst Lynn 
Published: February 2023

Summary

This thesis describes multiple central and peripheral immune cell changes during aging, in Alzheimer’s disease (AD), and multiple sclerosis (MS). In the first chapters of this thesis, we investigated the effect of aging on the immune system and searched for the aging factors involved. In the later chapters, we investigated the immune response to AD and MS pathology.

Aging

During aging, a general decline in immune function occurs, ultimately contributing to increased susceptibility to infections in the elderly. We found that microglial morphological complexity declines during aging and can be modulated by peripheral levels of glucocorticoids. We further discovered that peripheral factors can induce age-associated changes in the brain, and thus potentially counteract them. Consequently, we hypothesize that modulating peripheral immunity via plasma factors, such as hormones and cytokines, could combat brain aging and associated pathology.

Alzheimer’s disease

AD is a neurodegenerative disease that ultimately causes dementia. One of the pathological hallmarks is the deposition of abnormal tau protein in the brain. We found that this deposition induced reactive and dystrophic microglia with increased lysosomal volumes containing abnormal tau and postsynaptic structures. Together, this shows that tauopathy induces a loss of homeostatic microglia that is potentially linked to a loss of synapses.

Peripheral immune cells are associated with neurodegenerative diseases as well, although fewer research attempts have investigated these cells in the context of AD. We analyzed the peripheral immune landscape of AD patients at the early and late stages of the disease and found that levels of circulating CD8+ T cells with an effector memory phenotype increased before the onset of dementia. These CD8+ T cells expressed markers associated with T cell senescence and terminal differentiation. We also found that carrying the apolipoprotein E (APOE)-4 allele, a genetic risk factor for AD, affected the expression of genes involved in lipid metabolism and T cell activation in circulating immune cells of AD patients. Together, our findings show that peripheral immune changes reflect the pathobiological events of AD.

Multiple sclerosis

MS is the most common chronic neurodegenerative and neuroinflammatory disease in young adults. Studies have shown that compartmentalized inflammation of the nearby leptomeninges in MS patients is associated with many aspects of cortical pathology. Still, the pathological mechanisms of meningeal inflammation-induced cortical pathology remain largely elusive. We identified two MS-specific cortical microglial populations that were associated with meningeal inflammation and neurodegeneration in post-mortem progressive MS tissue. We hypothesize that microglia initially protect neurons from meningeal inflammation-induced cell death but eventually lose these protective properties and contribute to neuronal loss.

In addition, studies have shown that MS patients have increased levels of immune cells and inflammatory factors in their cerebrospinal fluid (CSF). Periventricular regions around the CSF are hotspots for MS lesions, and these lesions correlate to cortical thinning. We show the infiltration of T cells, antibody-secreting cells, and NK cells in the periventricular brain regions of MS donors. The periventricular NK cells displayed an activated and migratory phenotype in MS donors, similar to their circulating counterparts. Potentially, this reflects ongoing NK cell migration to the brain parenchyma via the CSF and periventricular brain regions in MS patients.

Conclusion

In this thesis, we uncovered several aspects of the peripheral and central immune response to pathobiological events during aging, in AD, and in MS. I hope that our findings, together with upcoming studies, will lead to the generation of novel immune therapies that slow or prevent neurodegeneration and cognitive decline.