Alterations in the transcriptional profile of genes related to glutamatergic signalling in animal models of Alzheimer's disease. The effect of fingolimod.

Alzheimer's disease (AD) is a multi-factorial illness that leads to progressive cognitive impairment. A glutamatergic system dysfunction has been reported to be implicated in the pathomechanism of AD. Therefore, in the current study we characterized the transcriptional profile of glutamate-related genes in transgenic AbPP V717I (TgAD) and sporadic (SAD, streptozotocin-induced) models of AD. Genes encoding glutamate membrane-bound (GLAST, GLT1, EAAC1) and vesicular (VGLUT1-3) transporters as well as ionotropic (AMPA, NMDA) and metabotropic (mGluR3, mGluR5) receptors were analysed. Based on qPCR analysis, we observed a discrepancy between TgAD and SAD mice in the profile of targeted genes. We noticed age-dependent upregulation of genes encoding VGLUT1, NMDAR1 and mGluR3 in 12-month-old TgAD mice. In the SAD model upregulation of genes encoding AMPAR1 and NMDAR1 as well as downregulation of GLAST, VGLUT3 and mGluR5 were found. Next, the effect of fingolimod (FTY720) was indicated. In the TgAD model, the drug reversed altered transcription of the mGluR3 glutamate receptor to the control level, whereas in the SAD model it downregulated the genes encoding VGLUT1, AMPAR2 and mGluR3. Interestingly, FTY720 influenced mGluR3 mRNA in both examined models. Observed alterations of gene transcription and the effects of FTY720 may potentially constitute an interesting target for further pharmacological studies.