Early neuronal dysfunction by amyloid ß oligomers depends on activation of NR2B-containing NMDA receptors.

Several studies indicate that NMDA receptor signaling is involved in Aß oligomer-mediated impairment of neuronal function and morphology. Utilizing primary neuronal cell culture and hippocampal slices from rat and mouse, we found that Aß oligomer administration readily impairs long-term potentiation, reduces baseline synaptic transmission, decreases neuronal spontaneous network activity and induces retraction of synaptic contacts long before major cytotoxic effects are visible. Interestingly, all these effects can be blocked with the NR2B-containing NMDA-receptor antagonist ifenprodil or Ro 25-6981 suggesting that activation of downstream effectors of these receptors is involved in early detrimental actions of Aß oligomers. In line we found that Jacob, a messenger that can couple extrasynaptic NMDA-receptor activity to CREB dephosphorylation, accumulates in the nucleus after Aß oligomer administration and that the nuclear accumulation of Jacob can be blocked by a simultaneous application of ifenprodil. We conclude that Aß oligomers induce early neuronal dysfunction mainly by activation of NR2B-containing NMDA-receptors.

The influence of the branched-chain fatty acids pristanic acid and Refsum disease-associated phytanic acid on mitochondrial functions and calcium regulation of hippocampal neurons, astrocytes, and oligodendrocytes.

Pristanic acid and phytanic acid are branched-chain fatty acids, which play an important role in diseases with peroxisomal impairment, like Refsum disease (MIM 266500), Zellwegers syndrome and alpha-methylacyl-CoA racemase deficiency (MIM 604489). Several studies revealed that the toxic activity of phytanic acid is mediated by multiple mitochondrial dysfunctions. However, the action of pristanic acid on brain cells is still completely unknown. Here, we exposed astrocytes, oligodendrocytes and neurons in mixed culture to pristanic acid and phytanic acid to analyse cellular consequences. Pristanic acid exerts a strong cytotoxic activity on brain cells, displayed by dramatic Ca2+ deregulation, in situ mitochondrial depolarization and cell death. Interestingly, pristanic acid strongly induced generation of reactive oxygen species (ROS), whereas phytanic acid exerts weaker effects on ROS production. In conclusion, pristanic acid as well as phytanic acid induced a complex array of toxic activities with mitochondrial dysfunction and Ca2+ deregulation.