fig4

Figure 4. Initial loss of NE/LC neurons resulted from either LPS or DSP-4 injection renders neurons in the NE neuron-innervated regions more susceptible to inflammation-related damage. In normal condition (Left), NE released from the presynaptic terminals of LC/NE neurons performs multiple functions through different ways of transmission. During synaptic transmission, released NE functions as a neuromodulator by directly acting on postsynaptic β2-receptors to modulate the function of postsynaptic neurons. In volume transmission, extra-synaptic NE, diffused out of the synapse or released from dendrites, can act on other neighboring cells, such as microglia. NE exerts anti-inflammatory and neuroprotective functions through the inhibition of microglial NOX2. In pathological condition (Right), reduced NE release from LC/NE neurons not only disrupts the synaptic transmission, but also renders surrounding microglia prone to activation to release proinflammatory immune factors, leading to neuronal damage. Thus, we hypothesize that dysfunction of LC/NE neurons after LPS or DSP-4 injection renders neurons more sensitive to inflammation/oxidative insults and initiates neurodegeneration.