Inhibition of PDE4B ameliorates cognitive defects in the model of alcoholic dementia in 3×Tg-AD mice via PDE4B/cAMP/PKA signaling

Chronic, heavy alcohol use may lead to permanent brain damage, cognitive impairment, and dementia. One of the most serious consequences is alcoholic dementia (AlD). Phosphodiesterase-4 (PDE4) inhibitors have been shown to exhibit beneficial effects on cognition deficits and alcoholism. However, it is not known whether PDE4 inhibitors can be used to treat AlD. A33, a relatively selective PDE4B inhibitor, is absent of the emetic effect associated with PDE4D. The effect of A33 on memory and cognition in AlD remains unclear. We investigated the effects of A33 and the PDE4 inhibitor rolipram on memory and cognition using an AlD animal model, i.e., APP/PS1/Tau mice drinking alcohol in the two-bottle choice test, with or without A33 or rolipram treatment for 3 wk. The animal groups were compared in behavioral tests related to learning and memory. Neurochemical measures were conducted to explore the underlying mechanism of A33. Compared to WT controls, AlD mice showed impairments of learning ability and memory in the behavior tests; this was attenuated by treatment of rolipram or A33. In addition, administration of rolipram or A33 in AlD mice further alleviated neuropathological alterations in the hippocampus, including Aβ expression and deposition; rolipram or A33 also decreased the levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, as well as NF-κB. Further, rolipram or A33 decreased the activation of microglia while increased cAMP levels in the hippocampus of AlD mice. These results revealed that the alleviation of the cognitive impairment of AlD in APP/PS1/Tau triple transgenic mice by rolipram or A33 was linked to the action of the PDE4B/cAMP/PKA signaling pathway. A33 can be a promising therapeutic agent for AlD-related cognitive dysfunction.