Assessing Astrocytes in Alzheimer's Disease

Abstract

Alzheimer’s disease causes between 60% and 70% of all cases of dementia. Astrocytes maintain water, ion- and neurotransmitter homeostasis in a healthy brain, and they become reactive during Alzheimer’s disease. Astrocyte reactivity leads to a change in their morphology and their gene expression pattern, with among others an increased expression of GFAP and vimentin. The main hypothesis discussed in this thesis is that, when astrocytes become reactive, they neglect their normal functions and are less well equipped to take care of neurons, resulting in increased neuronal death. We worked on two questions: 1. What are the differences between astrocytes in a healthy and an Alzheimer’s disease brain? 2. If we can suppress astrocyte reactivity, will this result in a decrease in Alzheimer symptoms? To answer these questions, we used APP/PS1 mice, a commonly used mouse model for Alzheimer’s disease. We found that both brain region and sex have a large effect on the gene expression of astrocytes. However, we also found that Alzheimer’s disease, specifically the presence of amyloid plaques, only had a minor effect on astrocyte gene expression. One gene, however, SerpinA3N, was consistently upregulated in Alzheimer’s disease astrocytes. Furthermore, we found that suppressing astrocyte reactivity by knocking out GFAP and vimentin was insufficient to prevent the development of Alzheimer’s disease, as it did not reduce the production of Aβ-plaques, nor did it improve synaptic plasticity or rescue memory deficits. Together these results provide new information regarding the mechanisms underlying, and the involvement of astrocytes in Alzheimer’s disease.