Effect of C5a/C5aR on Glutamate Receptors and Glutamate Transporters expression in AD model mice

Identifier:  TFG:110

Handle: https://hdl.handle.net/20.500.11797/TFG110

Authors:  Sanz Castel, Eva

Abstract:
Effect of C5a/C5aR on Glutamate Receptors and Glutamate Transporters expression in AD model mice SUMMARY Alzheimer's disease is a clinically progressive dementia characterized by the accumulation of amyloid-b protein, neurofibrillary tangles, and neuronal loss. It is also associated with neuroinflammation, activation of microglia and astrocytes, and evidence of activation of the complement system. The Tenner Lab previously showed significant deficits in behavior in ArcticC5aGFAP mice and improvement in ArcticC5aRKO. Among amyloid beta plaques and activated microglia, there were only significant differences seen in the activated microglia, stained by its marker CD45. The IHC data did not correlate with the differences seen in the behavior of these models. Glutamate is a major excitatory neurotransmitter in the central nervous system and is known to be involved in synaptic transmission and plasticity, neuronal growth, and learning and memory. To further determine correlates of the loss of cognition ability in the AD mouse models, we study neuronal markers involved in memory and learning, focusing on those involved in glutamate signaling pathways. In the present study we validated previous findings of the amount of fibrillar plaques and recruited microglia using thioflavine staining and CD45 immunohistochemistry, respectively, in 7months Arctic/ArcticC5aGFAP and in 8.5months Arctic/ArcticC5aRKO. We then analyzed the expression of the glutamate receptor, GluR1, and its phosphorylated form, pGluR1, and two transporters, GLT1 and VGluT1, in hippocampal lysates of these transgenic mouse models of AD by Western Blot. Significant decreased expression of GluR1 and pGluR1 was observed which is in agreement with deficits in memory and learning seen in AD. We confirmed that there are no significant differences in fibrillar plaques or microglia staining between genotypes. On the basis of these results, we conclude that significant increase in pGluR1 levels of ArcticC5aRKO (compared to Arctic) suggests that the lack of C5aR is beneficial in this AD model. In addition, significant lower expression level of GluR1 in Arctic (compared to WT) agrees with poor cognition of AD model.