Many inhibitors of other PDE subtypes have been reported to produce cognitive enhancement (Reneerkens et al., 2009) and have been associated with neuronal cAMP signaling activation. Rolipram, a PDE4 inhibitor, reverses the decrease in cAMP regulatory element-binding protein (CREB) phosphorylation, which results in persistent improvement in synaptic function in AD model mice (Gong et al., 2004). Sildenafil, a PDE5 inhibitor, decreases Aβ levels in extracts of cerebral cortex and improves associative and spatial memory in AD model mice (Puzzo et al., 2009). Caffeine is a non-specific PDE inhibitor (Yoshimura, 2005), and its beneficial effects have been clarified in many clinical AD studies (Eskelinen et al., 2009; Eskelinen and Kivipelto, 2010). Caffeine stimulates cAMP-dependent protein kinase A signaling and increases CREB phosphorylation in AD model mice (Arendash et al., 2006; Zeitlin et al., 2011). Protein kinase A activation then suppresses the expression of Aβ-synthesizing enzymes such as β- and γ-secretase, leading to reduced Aβ production (Arendash et al., 2009). Cilostazol also reduces Aβ production in vitro (Lee et al., 2012, 2014; Maki et al., 2014), and suppresses Aβ-induced tauopathy and tau
