Expansion of activated resident subpopulations of astrocytes and microglia in the presence of amyloid pathology
Jonathon P. Sens1,2, Silvia S. Kang1,2, Mark T.W. Ebbert1,2, Aleksandra Wojtas1,2, Kelsey E. Baker1, Aishe Kurti1, Emily S. Norton1,2, Leonard Petrucelli1,2, John D. Fryer1,2*
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224; 2 Neurobiology of Disease graduate program of Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques that affect the function of diverse cellular populations within the brain. We have surveyed the transcriptome of individual cells in the cortex of a mouse model of amyloidosis (AD mice) and found a subpopulation of activated microglia that was significantly enriched in AD mice, with CCL3 and CCL4 as well as ApoE identified as network hubs. These “activated” microglia were significantly enriched for oxidative phosphorylation as well as ribosomes and translation, indicating that these cells have actively increased protein translational machinery. We also identified a subpopulation of activated astrocytes that was significantly elevated in AD mice, with biological networks centered on APP, PRNP, and ERK1/2. These “activated” astrocytes revealed significant enrichment in antibiotic synthesis, pH regulation, and lipid metabolism. Interestingly, these activated microglia or astrocyte subpopulations were also present, albeit less abundant, in wild-type controls, indicating that a subpopulation of these resident glial cells exists and may be the first to react to neurodegeneration. Several novel candidates identified by our transcriptomic profiling warrant further functional exploration in the context of amyloidosis. Furthermore, we will extend our study and survey the transcriptome of individual nuclei in human AD brain tissue as well as examining the role of aging in inflammatory processes by single cell transcriptomics in young and aged mice.