beta-amyloid inhibits hippocampal LTP through TNFR/IKK/NF-kappa B pathway

Objective: The suppressive action of the acute application of oligomeric amyloid-beta (A beta) on hippocampal long-term potentiation (LTP) has been reported widely. Many mechanisms have been proposed for A beta inhibited LTP induction. The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has also been reported to play a key role in this LTP inhibition through A beta. However, the underlying molecular mechanisms are largely unknown. This study aimed to investigate the link between A beta- and TNF-alpha-mediated hippocampal LTP inhibition. Methods: Acute hippocampal slices of male wildtype or Alzheimer's disease (AD) transgenic mouse models were treated with the inhibitors of either TNF-alpha, I kappa B Kinase (IKK) or Nuclear Factor-kappa B (NF-kappa B) in the presence or absence of oligomeric A beta(42) (500 nM/2 h). The LTP was assessed using field excitatory post synaptic potential recordings (fEPSP), and immunoblotting was used to evaluate the expression of IKK and NF-kappa B. Results: Acute treatment with A or TNF-alpha alone inhibited LTP and increased the phosphorylation of IKK and NF-kappa B in wild type mouse hippocampal slices. Pretreatment with TNF-alpha antagonist infliximab rescued the LTP impairment by A beta and also restored the levels of IKK and NF-kappa B to the control levels. In addition, pretreatment with IKK2 IV or JSH23 also restored the A beta-mediated LTP impairment. Furthermore, AD transgenic mouse hippocampal slices treated with infliximab or inhibitors of IKK or NF-kappa B showed improved LTP and reversed the activation of IKK and NF-kappa B. Conclusion: In conclusion, our observations suggest that the IKK/NF-kappa B signaling pathway play an important role in A-mediated hippocampal LTP impairment. A beta might modulate IKK/NF-kappa B activity by binding or activating tumor necrosis factor receptor (TNFR).