| dc.description.abstract |
Microglia comprise the resident tissue macrophage population in the brain parenchyma. They acquire a variety of functions in health and disease and are thus one of the most studied cell types regarding their contribution to neurological disease. In Alzheimer’s disease, deposition of amyloid-β occurs in senile plaques and leads to alterations of the microglial phenotype. This feature is mimicked in transgenic mouse models developing cerebral β-amyloidosis. How microglia influence onset and progression of Alzheimer’s disease remains incompletely understood despite many studies. Microglia are developmentally distinct from tissue macrophages in other organs and invade the brain early in embryogenesis. A long lifetime has been attributed to microglia; however, this has only scarcely been studied. Today, technological advances in the development of transgenic mouse models and in vivo microscopy allow for the in depth analysis of microglial turnover. In the first study presented here, we used genetic tools to label individual microglia and followed them in vivo by two-photon imaging. Long-term imaging over many months revealed that microglia are a long-lived cell population with low turnover rates. Furthermore, the rates of microglial proliferation and death were equal, matching previous reports that microglial cell numbers stay stable over time. In line with previous studies, higher proliferation rates were found in a mouse model of cerebral β-amyloidosis. Nevertheless, both in health and disease conditions, microglia lived many months and a proportion of microglia persisted throughout the entire lifespan of mice. The long lifetime of microglia renders them suitable for the characterization of innate immune memory, a recently emerged concept, in the brain. While it was previously believed that only adaptive immune cells depict memory characteristics, recent reports have demonstrated immune memory also in cells of the innate immune system. Herein, a priming immune stimulus leads to a long-lasting change in the activation state of the innate immune cell, thereby modifying its response towards a secondary stimulus. In particular, two paradigms can be distinguished: a heightened response has been termed training, while a reduced response is called tolerance. Our second study aimed to reveal whether training and tolerance are inducible in the brain and could be long-lasting modifiers of later occurring neurological disease pathology. We demonstrate that following peripheral immune stimulation with lipopolysaccharides or certain cytokines acute training and tolerance effects were evident in the brain. Furthermore, training and tolerance had opposing effects on much later occurring neuropathology of stroke and early stages of cerebral β-amyloidosis. Microglial enhancer landscape, gene expression, and function differed in response to peripheral immune stimulation with lipopolysaccharides, indicating long-term microglial reprogramming. Therefore, our study provides evidence for long-lasting innate immune memory in microglia that is epigenetically encoded and is sufficient to alter later developing neuropathology. In the third study, we investigated whether training and tolerance modify amyloid plaque structure and neurotoxicity in mice with more advanced cerebral β-amyloidosis. Strikingly, modifications of amyloid plaque structure were evident 9 months after induction of training and tolerance, and occurred concomitantly with alterations in microglial function. In particular, peripheral training and tolerance stimuli altered the phenotype of plaque-associated microglia or reduced their number, respectively. Both impaired microglial barrier function, a recently described feature of microglia around amyloid plaques in Alzheimer’s disease mouse models and patients. Importantly, modulation of microglial function, as induced by peripheral immune stimulation, altered amyloid plaque structure and thereby increased plaque-associated neurotoxicity. These results indicate that changes in microglial function contribute to neuronal damage by modulating amyloid structure and that such changes may occur in response to peripheral inflammatory events. In summary, this thesis demonstrates that microglia are exceptionally long-lived cells with the capability to form persisting immune memory. Peripheral immune stimulation epigenetically reprograms microglia to acquire distinct phenotypes that subsequently modify pathological features of cerebral β-amyloidosis. Therefore, we identified epigenetic microglial memory of peripheral inflammation as an essential modifier of neurological diseases. |
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