The brain, functionally dominated by neurons, relies on the support of non-neuronal cells for optimal function. Astrocytes play an important role in this system, such as by engaging with synapses to regulate neurotransmission, synaptic plasticity and ion homeostasis. In addition, microglia function as the immune cells of the brain, constantly monitoring the environment for damage or pathogens. While existing studies have shown the involvement of microglia and astrocyte reactivity in the progression of Alzheimer’s Disease (AD), the exact aetiology of events remains unanswered. This leaves the potential beneficial effect of the prevention of microglial or astrocytic reactivity to cognitive impairment as not fully addressed yet. In this thesis, I focused specifically on the early stages of AD in a mouse model and manipulated microglial and astrocytic reactivity to investigate the causal relationship with cognitive impairment in AD. In addition, I explored the spatial interaction between astrocytes and synapses, to understand its role in relation to memory impairment in AD and megalencephalic leukoencephalopathy with subcortical cysts (MLC). By using mouse models, I provided fundamental insights into the early phase of AD pathology. I showed a relation between both microglial reactivity and astrocytic reactivity with cognitive impairment. I found indications for a protective role against oxidative stress by astrocytes in early AD. In addition, I observed a deficit in astrocyte-synapse interactions in models of impaired memory, confirming the importance of a dynamic astrocyte-synapse interplay in memory formation. Altogether, these results strengthen the importance to include therapeutic strategies intervening at microglial and astrocytic reactivity in an early disease phase to positively affect Alzheimer disease outcome in the future.
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