Transcriptome analysis and in vivo calcium imaging of astrocytes in an Alzheimer’s Disease mouse model

Nelli Blank1, Stefanie Warnat-Herresthal2, Lech Kaczmarczyk1, Walker S. Jackson1, Joachim L. Schultze2, Gabor C. Petzold1

1 German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany
2 Department of Genomics and Immunoregulation, LIMES Institute, University of Bonn, 53115 Bonn, Germany

One of the most prominent hallmark of Alzheimer’s Disease (AD) is the accumulation of neurotoxic amyloid-beta (Aβ) species, which have the tendency to form extracellular insoluble Aβ plaques and induce reactive astrogliosis in surrounding astrocytes. In mice that develop Aβ pathology (AD mice), we have shown that peri-plaque astrocytes become hyperactive that was detected by a higher frequency of calcium events in the cortex of anesthetized mice. However, it has remained unclear how astrocytes and astrocytic hyperactivity contribute to the onset and progression of AD, and how astrocytic gene expression and cellular functions are altered in AD mice. To identify transcriptional alterations in astrocytes during disease progression and aging, we used the RiboTag technique in wild type compared to AD mice. Differential expression analysis uncovered an upregulation of surfaceome and secretome pathways involved in calcium signalling. To investigate if the consequences of these genetic alterations on functional changes in astrocytes of awake behaving mice, we performed longitudinal in vivo calcium imaging. For this purpose, we transduced astrocytes in APPPS1 and WT mice with AAV virus encoding for GCaMP6f, enabling us to measure spontaneous calcium transients and to correlate these data to behaviour and disease progression in. We detected a higher locomotion-induced calcium response in AD mice, indicating a potential contribution of calcium signalling pathways  in locomotion-associated network dysregulation.