ß-amyloid inhibits hippocampal LTP through TNFR/IKK/NF-κB pathway.

ABSTRACT

Objective The suppressive action of the acute application of oligomeric amyloid-ß (Aß) on hippocampal long-term potentiation (LTP) has been reported widely. Many mechanisms have been proposed for Aß inhibited LTP induction. The inflammatory cytokine tumor necrosis factor-α (TNF-α) has also been reported to play a key role in this LTP inhibition through Aß. However, the underlying molecular mechanisms are largely unknown. This study aimed to investigate the link between Aß- and TNF-α-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-α, IκB Kinase (IKK) or Nuclear Factor-κB (NF-κB) in the presence or absence of oligomeric Aß42 (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-κB. Results Acute treatment with Aß or TNF-α alone inhibited LTP and increased the phosphorylation of IKK and NF-κB in wild type mouse hippocampal slices. Pretreatment with TNF-α antagonist infliximab rescued the LTP impairment by Aß and also restored the levels of IKK and NF-κB to the control levels. In addition, pretreatment with IKK2 IV or JSH23 also restored the Aß-mediated LTP impairment. Furthermore, AD transgenic mouse hippocampal slices treated with infliximab or inhibitors of IKK or NF-κB showed improved LTP and reversed the activation of IKK and NF-κB. Conclusion In conclusion, our observations suggest that the IKK/NF-κB signaling pathway play an important role in Aß-mediated hippocampal LTP impairment. Aß might modulate IKK/NF-κB activity by binding or activating tumor necrosis factor receptor (TNFR).