Cellular Vulnerability in the Early Stage of Alzheimer’s Disease Revealed by Single-Cell Transcriptomics

It is increasingly clear that in the course of Alzheimer disease a long period of action and reaction occurs between the first appearance of the biochemical lesions (amyloid plaques and tangles) and the clinical dementia. This phase encompasses cellular reactions and many different molecular pathways. We know indeed that several molecular pathways and genes are critically involved in the pathogenesis of Alzheimer disease including the amyloid and Tau biochemical pathways. However, little is known which cells and at what time in the course of the disease these genes are expressed. Moreover, it is very likely that additional genes and pathways are expressed in cell specific ways that remain undetected and are important in the pathogenesis of the disorder. In the current project we want to initiate the study of the complex prodromal, cellular phase of Alzheimer disease by starting to chart the initial cellular reactions on A βstress in the hippocampus as discussed in a recent review of the lab (‘The cellular phase of Alzheimer’s disease’, Cell, 2016). The goal is to provide proof of concept and a basis for further similar studies in human and mouse models. We aim to initiate novel functional research addressing the role of these pathways in the development of the disease. It is expected that this work will lead to insights in the cellular phase of Alzheimer disease, to a more comprehensive approach to study the disorder and that such work will yield novel drug targets.