mSOD1G93A/PU.1−/− mice transplanted with wild-type bone marrow had wild-type find more microglia throughout the parenchyma, while mSOD1G93A/PU.1−/− mice transplanted

with mSOD1G93A bone marrow had mSOD1G93A microglia throughout the parenchyma. The mSOD1G93A/PU.1−/− transgenic mice with mSOD1G93A parenchymal microglia died considerably earlier and had greater motor neuron loss and shorter disease duration than the doubly transgenic mice with wild-type parenchymal microglia (19). Thus the ability of activated mSOD1 microglia to induce motor Inhibitors,research,lifescience,medical neuron injury in vitro was comparable to the mSOD1 microglia-mediated motor neuron injury in vivo, and most likely resulted from microglial-mediated release of neurotoxic substances and decreased release of neuroprotective factors. Conversely wild-type microglia mediated

relative neuroprotection both in vitro Inhibitors,research,lifescience,medical and in vivo. Summary: the Relevance of Neuroinflammation to ALS Pathogenesis The major themes in ALS pathogenesis are depicted in Figure 2. Evidence from the mSOD1 transgenic mouse suggests that alterations in distal motor axons are among the Inhibitors,research,lifescience,medical earliest pathological changes in the pathogenesis of ALS, and the process is best explained as “dying back.” End-plate denervation is noted prior to the evidence of ventral root or cell body loss, and prior to the appearance of activated microglia surrounding affected motor neurons (20). In ALS patients, mitochondrial alterations consisting of swelling and increased calcium are present in motor axon terminals at early stages (21). Thus alterations in synaptic function and axonal connectivity may represent early and critical pathogenic events in ALS. Subsequent changes in axonal transport are also early events in ALS, impairing Inhibitors,research,lifescience,medical the transport of newly synthesized proteins and lipids and Inhibitors,research,lifescience,medical the clearance of damaged or misfolded proteins (22). A significant decrease in retrograde survival factors, including P-Trk (phospho-Trk)

and P-Erk1/2, and an increase in retrograde stress factor signaling, including P-JNK (phosphorylated c-Jun N-terminal kinase), caspase-8, and p75(NTR) cleavage fragment have been documented in the mSOD1 transgenic mouse (23). Thus a shift from survival-promoting to death-promoting retrograde signaling may be a key step leading to neurodegeneration in ALS. This switch from survival-promoting to deathpromoting does not occur in mSOD1 motor neurons in vitro unless they are maintained on mSOD1 Adenylyl cyclase supporting cells. Thus, the evidence for non-cell autonomy necessitates the conclusion that changes within the neuron itself are insufficient to cause motor neuron death, but require motor-neuron–microglia signaling at least at the level of the cell soma. Whether the axonal death-promoting signaling is directly responsible for triggering ER stress, which further exacerbates the unfolded protein response and activates caspases, is unclear.