Transcriptional signatures of microglial innate immune memory in models of Parkinson’s and Huntington’s disease

Abstract

Due to the ever-increasing age of the human population, the absolute number of individuals impacted by neurodegenerative diseases has been growing globally for the last 25 years. As most of them are currently incurable, neurological disorders are the primary cause of disability and death worldwide. Thus, a detailed understanding of the underlying processes of neurodegenerative disorders and the search for therapies are becoming increasingly urgent tasks. Parkinson’s disease (PD) and Huntington’s disease (HD) are chronic neurodegenerative conditions with neuronal loss in the motor, sensory, and cognitive systems. Increasing evidence indicates that neuroinflammation plays a substantial role in the pathogenesis of various neurodegenerative disorders. Therefore, it is crucial to understand how exactly the brain’s immune system affects neuropathology and whether environmental factors that change the immune system response could be risk factors for neurodegenerative diseases. Recent research revealed that innate immune memory in microglia could shape cerebral β-amyloidosis in an AD mouse model and can modify brain cytokine levels, microglial epigenetic and gene expression profiles, metabolism, and phagocytic activity for at least 6 months. However, whether microglial immune memory influences disease pathogenesis in models of PD and HD remains unknown. Therefore, the aim of this thesis was to investigate the effect of innate immune memory on microglial transcriptomic profiles in PD and HD rat models. To this end, two well-characterized rat models of a-synucleinopathy or mutant huntingtin (mHTT) pathology, the neuropathological hallmarks of PD or HD, respectively, were used. The first set of experiments of my thesis focused on investigating whether immune memory can be induced in the blood and brain by peripheral immune stimuli (using one, two, or four injections of bacterial lipopolysaccharides) and a high-fat diet in PD and HD rat models. The second set of experiments of my thesis focused on investigating whether immune memory triggered by peripheral stimuli and a high-fat diet is apparent in the microglial transcriptomic profiles in PD and HD rat models. The third set of experiments of my thesis focused on the heterogeneity of microglial cells in 9- month-old BAC HD and BAC SNCA rats using single-cell RNA-sequencing (scRNA-seq). The findings of my thesis support the existence of innate immune memory in microglia across a variety of disease models and species and provide the first evidence that the same initial immune stimulus causes brain pathology-specific modulation of transcriptomic responses in microglia (as evidenced by different molecular pathways being modulated in PD vs HD models here). The results of the single-cell experiments suggest for the first time that only specific microglial subpopulations react in the early stages of PD and HD pathology; whether these cells are associated with driving or preventing pathology requires further investigation.