Aβ oligomers from human brain impair mossy fiber LTP in CA3 of hippocampus, but activating cAMP-PKA and cGMP-PKG prevents this.

Early cognitive impairment in Alzheimer's disease may result in part from synaptic dysfunction caused by the accumulation oligomeric assemblies of amyloid β-protein (Aβ). Changes in hippocampal function seem critical for cognitive impairment in early Alzheimer's disease (AD). Diffusible oligomers of Aβ (oAβ) have been shown to block canonical long-term potentiation (LTP) in the CA1 area of hippocampus, but whether there is also a direct effect of oAβ on synaptic transmission and plasticity at synapses between mossy fibers (axons) from the dentate gyrus granule cells and CA3 pyramidal neurons (mf-CA3 synapses) is unknown. Studies in APP transgenic mice have suggested an age-dependent impairment of mossy fiber LTP. Here we report that although endogenous AD brain-derived soluble oAβ had no effect on mossy-fiber basal transmission, it strongly impaired paired-pulse facilitation in the mossy fiber pathway and presynaptic mossy fiber LTP (mf-LTP). Selective activation of both β1 and β2 adrenergic receptors and their downstream cAMP/PKA signaling pathway prevented oAβ-mediated inhibition of mf-LTP. Unexpectedly, activation of the cGMP/PKG signaling pathway also prevented oAβ-impaired mf-LTP. Our results reveal certain specific pharmacological targets to ameliorate human oAβ-mediated impairment at the mf-CA3 synapse.