Stimulus pattern dependence of the Alzheimer's disease amyloid-β 42 peptide's inhibition of long term potentiation in mouse hippocampal slices

Increasing evidence has pointed to inhibition of Long Term Potentiation (LTP) by soluble Aβ42 oligomers as central in the etiology of the learning and memory deficits that are hallmarks of Alzheimer Disease. These effects are thought to occur by an interaction between Aβ42 and certain cellular effectors that induce LTP, however, the precise identity of the Aβ42-interactive signaling molecules is unknown. Identification of such effectors is made more difficult because LTP induced by different stimulation protocols can be expressed through heterogeneous signaling pathways. The aim of this study was to compare differences in the Aβ42-dependent levels of inhibition of LTPs that were induced using high frequency stimulation (HFS), versus theta burst stimulation (TBS). Our results show that untreated control brain slices tetanized with either HFS or TBS gave similar levels of LTP and post tetanic stimulation (PTP), suggesting that the response induced by either protocol was comparable. However, Aβ42 peptide significantly blocked LTP and PTP induced by HFS, but not when TBS was used. NMDA receptor antagonists, D-AP5 and ifenprodil, both blocked LTPs that were induced by HFS or TBS. We propose that unknown signaling effectors, other than the NMDA receptor, which are differentially involved in the induction of LTP by TBS, as compared to HFS, may be responsible for this resistance of TBS-induced LTP to Aβ42 dependent inhibition.