Strong evidence implicates the complement pathway as an important contributor to amyloid pathology in Alzheimer's disease (AD); however, the role of complement in tau modulation remains unclear. Here we show that the expression of C3 and C3a receptor (C3aR1) are positively correlated with cognitive decline and Braak staging in human AD brains. Deletion of C3ar1 in PS19 mice results in the rescue of tau pathology and attenuation of neuroinflammation, synaptic deficits, and neurodegeneration. Through RNA sequencing and cell-type-specific transcriptomic analysis, we identify a C3aR-dependent transcription factor network that regulates a reactive glial switch whose inactivation ameliorates disease-associated microglia and neurotoxic astrocyte signatures. Strikingly, this C3aR network includes multiple genes linked to late-onset AD. Mechanistically, we identify STAT3 as a direct target of C3-C3aR signaling that functionally mediates tau pathogenesis. All together our findings demonstrate a crucial role for activation of the C3-C3aR network in mediating neuroinflammation and tau pathology.
Pubmed ID: 30415998 RIS Download
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View all literature mentionsSoftware package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.
View all literature mentionsManually curated database of eukaryotic transcription factors, their genomic binding sites and DNA binding profiles. Used to predict potential transcription factor binding sites.
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View all literature mentionsMus musculus with name C.129S4-C3ar1tm1Cge/J from IMSR.
View all literature mentionsStereo Investigator system includes microscope, computer, and Stereo Investigator software. Software works with Brightfield, Multi-Channel Fluorescence, Confocal, and Structured Illumination Microscopes. System used to provide estimates of number, length, area, and volume of cells or biological structures in tissue specimen in areas of neuroscience including neurodegenerative diseases, neuropathy, memory, and behavior, pulmonary research, spinal cord research, and toxicology.
View all literature mentionsCell line BV-2 is a Transformed cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsSoftware package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.
View all literature mentionsMus musculus with name C.129S4-C3ar1tm1Cge/J from IMSR.
View all literature mentionsMus musculus with name B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J from IMSR.
View all literature mentionsThis monoclonal targets C3aR Rat mAb 74
View all literature mentionsCell line BV-2 is a Transformed cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsThis monoclonal targets Syp
View all literature mentionsThis monoclonal targets Glial Fibrillary Acidic Protein (GFAP)
View all literature mentionsThis monoclonal targets Phospho-Stat3 (Tyr705)
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