Neuroinflammation, Serotonergic Neurotransmission, and Alzheimer's Disease Event

Given that Alzheimer’s disease (AD) pathology develops years before the diagnosis can be made, clarification of the pathogenic mechanisms and of how to intervene in pathogenic cascade has huge therapeutic implications. Our research focuses on the involvement of microglia, neuroinflammation and serotonergic neurotransmission in AD pathogenesis. In the entorhinal cortex of AD subjects not only neuronal, but also microglial numbers are reduced, raising the question whether the microglia themselves succumb to the disease process. We also have evidence of a dysregulation of the microglial apoptosis in aging APPswe/PS1dE9 transgenic mice, although in these transgenics, the microglial population in the neocortex expands. Somewhat disappointing, results by others showing that serotonin and treatment with selective serotonin reuptake inhibitors (SSRI) ameliorate amyloid-β pathology in APPswe/PS1dE9 transgenic mice, are not supported by several lines of results from our laboratory. This does not necessarily mean, however, that the decline of the   serotonergic system has no influence on AD pathogenesis. Effects could be mediated by influencing microglial ability to handle and clear amyloid-β, which we currently investigate. New data suggesting an inverse correlation between [3H]DASB binding to the serotonin transporter, SERT, and [3H]PK11195 binding to TSPO will be presented, along with binding data from AD and non-AD subjects. Recently, we have also used proteomics strategies to investigate which pathway are activated in cortex from AD and non-AD subjects, in our transgenic AD model, in microglial cultures and microglial BV2 cultures. Data from these studies will also be presented and discussed.