Tracing the signals: Unravelling neuron-glia interactions in Alzheimer’s disease

Abstract

The brain consists of various cell types, including neurons, astrocytes, and microglia. Neurons are important for signal transduction and responsible for the communication within and between brain areas. Astrocytes and microglia fulfill a neuronal-support function by regulating a large variety of processes. Here, we used an Alzheimer’s disease (AD) mouse model to examine how the interaction between these cell types is affected during the preclinical phase of AD. The preclinical phase of AD is characterized by deposits of a specific protein in the brain, called amyloid-ß (Aß). Aß deposits trigger an inflammatory response in astrocytes and microglia. This has major consequences for their shape and function and ultimately negatively impacts neuronal activity and the connections between brain regions. The results presented here indicate that the inflammatory response, particularly in microglia, contributes to the earliest symptoms of AD, including impaired communication between neurons and impaired memory. We also show that these symptoms are reduced by suppressing the inflammatory response in microglia at an early stage of AD development. In contrast, astrocytes appear to be capable of executing important neuronal-support functions even in the presence of early AD pathology, and their inflammatory response therefore seems to have fewer implications for early AD development. Our research furthermore highlights the importance of peripheral agents as risk factors for the development of symptoms associated with AD. Overall, the results presented in this thesis provide highly relevant fundamental and translational insights into the pathophysiological basis of early AD pathology and the involvement of astrocyte and microglia reactivity in this. The results provide important directions for future study. Based on the results of this thesis, a growing focus on the role of microglia in especially the preclinical phase of AD would be appropriate. With more research, prevention or treatment of AD may be possible in the future, improving the quality of life of countless AD patients worldwide.