Because A1s are induced after injury and by LPS (a well-described neurodegeneration sensitizer that causes extensive neuroinflammation25,26), and because reactive microglia are found in neurodegenerative diseases, we investigated whether A1s are present in human neuroinflammatory and neurodegenerative diseases. Because complement component C3 is one of the most characteristic and highly upregulated genes in A1s and is not expressed by ischemic A2 reactive astrocytes (Extended Data Fig. 10), we carried out in-situ hybridization and immunochemistry on post-mortem tissue from patients with Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Multiple Sclerosis (MS) to identify whether there are C3-expressing A1 astrocytes in these diseases. We found many GFAP and S100β positive astrocytes that were C3 positive (either in situ or immunofluorescent) in regions traditionally associated with each disease (Fig. 5), and qPCR analysis confirmed upregulation of C3 in postmortem tissue samples. In demyelinating lesions of MS, C3-positive astrocytes were typically closely associated with CD68 positive activated microglia/macrophages (Fig. 5; Extended Data Fig. 11). In human AD, nearly 60% of GFAP positive astrocytes in the prefrontal cortex
