The hypothesis that activation of CREB through NO/cGMP signaling might modify the amyloid-β (Aβ) neuropathology, linked to AD pathogenesis, was demonstrated in both APP/PS1 and 3xTg transgenic mouse models of AD using small molecules, termed nomethiazoles, also designed to provide neuroprotection and attenuate pro-inflammatory cytokine release. Functional restoration of long-term potentiation was shown in hippocampal slices from AD transgenic mice in accord with observation of restoration of cognitive function in vivo, and was dependent upon soluble guanylyl cyclase (sGC) activation. Levels of pCREB and BDNF were significantly elevated, whereas TNFα, Aβ, oligomeric Aβ1-42, and also tau protein were significantly lowered after drug treatment. In the absence of neuronal loss in animal models of AD, neuroprotection was demonstrated in rat primary neurons after oxygen-glucose deprivation or application of oligomeric Aβ. The lead nomethiazole was also studied in a novel transgenic mouse model, E4FAD, which incorporates familial AD mutations, but also has targeted replacement of mouse apolipoprotein-E with human ApoE4, the major genetic risk factor for sporadic and age-related AD.