The presence of activated microglia, astrogliosis, and infiltrating lymphocytes accompanying motor neuron injury in ALS spinal cord tissue

has raised the question as to whether motor neuron cell loss is dictated solely by intracellular events – cell-autonomous – or whether other cells may be involved. This question cannot be answered directly from human studies, but has been addressed in the transgenic mouse model of ALS overexpressing a human mutation of Cu2+Zn2+ superoxide dismutase (mSOD1) (1). In both human ALS and the transgenic mSOD1 mouse, there is evidence of neuroinflammation Inhibitors,research,lifescience,medical with increased microglial activation as well as increased CD4 and CD8 T cells and dendritic cells (2, 3). Expression of the mSOD1 transgene in motor neurons alone is not sufficient to cause motor neuron injury (4). SAHA HDAC Further, expression solely in astrocytes or microglia does not lead to a motor neuron phenotype. Thus motor neurons do not die alone. To cause significant injury, mSOD1 must

be expressed in motor neurons as Inhibitors,research,lifescience,medical well as surrounding cells. This non-cell autonomy suggests a potential contribution Inhibitors,research,lifescience,medical of non-motor neuron cells such as microglia to motor neuron protection as well as motor neuron injury and cell death. Motor Neuron-Microglia Neuroprotective Signaling Motor neurons have been documented to promote microglia-mediated neuroprotection through at least two signals, fractalkine and CD200. The neuroprotective state of microglia characteristically releases anti-inflammatory selleck bio cytokines and neurotrophic factors (Fig. 1). Microglia are the only CNS cells that express the fractalkine receptor (CX3CR1).

Based on complementary expression of fractalkine (CX3CL1) on neurons and CX3CR1 Inhibitors,research,lifescience,medical on microglia, it had been proposed Inhibitors,research,lifescience,medical that neuroprotective signaling from motor neuron to microglia might be mediated through this receptor. In vivo, CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, CX3CR1-/- mice showed Batimastat cell-autonomous microglial neurotoxicity (5). Doubly transgenic mSOD/ CX3CR1-/-mice exhibited more extensive neuronal cell loss than CX3CR1+ littermate controls. Thus fractalkine release from motor neurons enhances neuroprotection, and the loss of the fractalkine receptor on microglia enhances neurotoxicity. Mice deficient for CD200, a neuronal glycoprotein whose receptor, CD200R, is expressed by all myeloid cells, show aberrant microglial physiology including morphological activation of microglia in the resting CNS and accelerated response to facial nerve transection (6). None of these attributes of altered microglial function are observed in CX3CR1-/- mice, indicating different neuroprotective pathways for CD200/CD200R and CX3CL1/CX3CR1 in regulating microglia. Figure 1.