Tissue Plasminogen Activator (tPA) Mediates Neurotoxin-Induced Cell Death and Microglial Activation.

摘要

Neuronal death occurs in the brain during development and in pathological conditions, like Alzheimer's disease and stroke. Tissue plasminogen activator (tPA), a protease converting plasminogen to plasmin, is necessary for neurodegeneration. In mice lacking tPA (tPA-/1), neurons are resistant to neurotoxic death. Delivery of tPA into tpA-/- mice restores susceptibility to neuronal death, indicating that tPA is neurotoxic in the context of excitotoxic injury. Although tPA is synthesized by neurons, the increase in tPA upon injury derives primarily from activated microglia, the immune cells of the brain. Microglia in tPA-/- mice demonstrate reduced activation. Using tPA as tool, we are determining whether microglia are neuroprotective or neurotoxic, and what are the cell types involved in the sequence of events that lead from injury to neuronal death. We have established primary cultures and obtained information from them on the source of tPA that initiates neurotoxin-induced cell death (Spec. aim 2), and have narrowed the region of tPA that promotes microglial activation (Spec. aim 1). Since exaggerated neurodegeneration is evident in pathological conditions, understanding the underlying mechanisms could prove beneficial for interfering with the pathologies.