The Diphasic Effect Ofalzheimer-Like Tau Pathology And Space Memory Inducing By Flurocitrate And Its Underlying Mechanisms

Background Interactions between neurons and glial cells in the brain may serveimportant functions. Fast neuron-glia synaptic transmission has been found betweenhippocampal neurons and NG2cells, a distinct population of microglia like cellswidely distributed in the brain. These neuron-glia synapses undergoactivity-dependent modifications analogous to long-term potentiation (LTP) atexcitatory synapses, a hallmark of neuronal plasticity. Glial cells in the spinal dorsalhorn play a role in the induction and maintenance of pathological pain due toinflammation and/or nerve injury. In Alzheimer’s disease (AD), a wall of reactiveastrocytes typically surrounds senile plaques of β-amyloid (Aβ).Astrocytes participatein β-amyloid clearance and degradation, provide trophic support to neurons, and forma protective barrier between Aβ deposits and neurons. Functional hemichannels thathave a role in glutamate homeostasis may significantly contribute toastrocyte-mediated regulation of neuronal activity. Fluorocitrate suggested selectivelyimpaired astrocyte metabolism.Whether and how flurocitrate may cause AD-like tauhyperphosphorylation and space memory injury are not known.Objective To investigate damage of astrocyte leads to dysregulated neuronal byfluorocitrate treatment.Methods We investigated the synaptic transmission by measuring long termpotentiation and spatial memory by measuring Morris water maze after fluorocitratetreatment. Tau phosphorylation, protein kinases and protein phosphatases andmemory-related proteins were examined with western blotting after fluorocitratetreatment in primary astrocytes, primary neurons and rats.ResultsAstrocyte induces tau hyperphosphorylation and LTP defcit after flurocitrate treatment in1h, and tau dephosphorylation space memory improvementafter fluorocitrate treatment in48h. The activity of PP2AandAKT was decreased in1h and were recovered in48h after fluorocitrate treatment, which was similar with tauhyperphosphorylation in1h and dephosphorylation in48h after fluorocitrate treatment,and which were similar with LTP defcit in1h and space memory improvement in48hafter fluorocitrate treatment. Fluorocitrate treatment causes LTP defcit in1h andspace memory improvemen in48h by affecting multiple synapse-associated and othermemory-associated proteins.Conclusion Astrocytes regulate space memory through regulating multiplesynapse-associate proteins andAlzheimer-like tau phosphorylation.