These findings raise important questions. First, what is the identity of the neurotoxin? We are presently using biochemical approaches to purify and characterize it. Second, to what extent are A1s present in spinal cord injury, CNS brain trauma, and other neuroinflammatory and neurodegenerative diseases, and are A1s actively driving death of neurons, axons, and synapses and/or oligodendrocytes in these diseases? Astrocytes have been found to be toxic to spinal motor neurons in ALS30,31 – do they have an A1 phenotype? In Alzheimer’s disease, oligomeric amyloid beta is a strong activator of microglia32 and our findings provide evidence that A1s are present in regions of neurodegeneration in human post mortem tissue. Although we found that activated microglia were insufficient by themselves to kill neurons, they strongly induce A1s, which could drive neurodegeneration not only by secreting a neurotoxin but by releasing multiple complement components that help to drive synapse degeneration33. In acute relapsing and remitting MS, we also observed C3-expressing A1s in demyelinating plaques. This suggests the possibility that demyelinating lesions, which generally also contain unmyelinated axons and OPCs, fail to
