Here we have identified A1 neurotoxic reactive astrocyte formation as a fundamental pathological response of the CNS to LPS-induced neuroinflammation, acute CNS injury, and most or all neurodegenerative diseases. Our findings identify a new role for activated microglia in inducing A1s via secretion of Il-1α, TNFα, and C1q in vitro and in vivo. In contrast to A2 reactive astrocytes, which are induced by ischemia5 and strongly promote neuronal survival and tissue repair10,27–29, A1s secrete a neurotoxin that induces rapid death of neurons and oligodendrocytes. A1s have lost many characteristic astrocyte functions including: ability to promote neuronal survival and outgrowth, promote synapse formation and function, and to phagocytose synapses and myelin debris. A1s are rapidly induced after acute CNS injury and responsible for the death of axotomized RGCs. A1s are also highly present in neurodegenerative diseases where their presence may well contribute to neurodegeneration and help to drive disease progression.
