Intraneuronally injected amyloid beta inhibits long-term potentiation in rat hippocampal slices

Extracellular accumulation of amyloid beta (Aβ) is a hallmark of Alzheimer's disease (AD). It has been reported that extracellular perfusion of Aβ inhibits long-term potentiation (LTP), which is strongly related to memory in animal models. However, it has recently been proposed that intracellular Aβ may be the first pathological change to occur in AD. Here, we have investigated the effect on LTP of intracellular injection of Aβ (Aβ_1-40, Aβ_1-42) into hippocampal pyramidal cells using patch-clamp technique. We found that injection of 1 nM Aβ_1-42 completely blocked LTP, and extracellular perfusion of a p38 MAPK inhibitor or a metabotropic glutamate receptor blocker reversed these blocking effects on LTP. Furthermore, we have examined the effects of different concentrations of Aβ_1-40 and Aβ_1-42 on LTP and showed that Aβ_1-40 required a 1,000-fold higher concentration to attenuate LTP than 1 nM Aβ_1-42. These results indicate that LTP is impaired by Aβ injected into genetically wild-type neurons in the sliced hippocampus, suggesting an acute action of intracellular Aβ on the intracellular LTP-inducing machinery.